Management of clozapine-resistant schizophrenia

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The incidence of treatment resistance in schizophrenia (failureto respond to antipsychotic therapy) is about 20%. Factors thatmay contribute to it include non-adherence (non-compliance)to treatment, comorbid conditions and medication side-effects.The National Institute for Clinical Excellence recommends thatclozapine be used for schizophrenia resistant to another atypicalantipsychotic. Here we focus on patients who are also resistantto clozapine given in adequate dosage for sufficient duration.Switching from clozapine to a previously untried atypical (e.g.olanzapine, risperidone, quetiapine) might be of benefit inpartial treatment resistance. In more difficult cases, augmentationof clozapine with benzamides (sulpiride, amisulpride) and anti-epileptics(lamotrigine) shows some success. In extreme treatment resistance,a strategy is recommended that combines the proven best drugfor the particular patient and psychosocial treatments.

In general, all patients with schizophrenia could be consideredtreatment resistant, since full remission is unusual in thisdisorder. In order to create specific treatment algorithms forpatients that are more difficult to treat, it is necessary todefine treatment resistance. Kane (1996) specified the followingcriteria for treatment resistance:

available medications and other treatments are not useful inalleviating the target symptoms of schizophrenia (not only thepositive and negative symptoms, but also disorganised or violent/aggressivebehaviour, thought disorder and suicidal ideation);
occurrenceof adverse side-effects of medication;
non-adherence to currenttreatment;
presence of comorbid conditions such as substancemisuse;
failure of maintenance and relapse despite seeminglyadequatedoses of antipsychotics.

In addition, arbitrary defining criteria include failure torespond to at least two neuroleptic drugs equivalent to 600mgchlorpromazine per day for more than 4 weeks (Juarez-Reyes etal, 1995). In clinical trial and audit settings, the most frequentlyused criteria are those adopted by Kane et al(1988) for theirseminal trial of clozapine v. chlorpromazine in treatment-refractoryschizophrenia. In this trial, patients were classified as resistantto treatment if:

they had not demonstrated improvement after three periods oftreatment with neuroleptics (from two or more different chemicalclasses) in the previous 5 years equivalent to 1000mg per dayof chlorpromazine for 6 weeks;
patients had had no episodesof good functioning in the previous5 years.

Using these criteria, Kane et al found the incidence of treatmentresistance in schizophrenia to be 20%.

Management with clozapine

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Management with clozapine

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This article focuses principally on the pharmacological managementof treatment resistance. However, before initiating clozapinetherapy, some basic principles should be adhered to, such asassessing non-adherence, re-evaluating the diagnosis, consideringorganic contributions to the diagnosis and assessing comorbidity(Morrison, 1996).

The evidence for clozapine as a superior treatment for schizophreniais consistent and is the subject of a number of reviews andmeta-analyses (Kane, 1992; Meltzer, 1992; Brambilla et al, 2002;Iqbal et al, 2003). Primary references for clozapine’ssuperior efficacy are cited in these reviews, but pivotal publicationsinclude a clinical trial of its use in treatment-resistant schizophrenia(Kane et al, 1988) and a meta-analysis of randomised controlledtrials of clozapine (Wahlbeck et al, 1999).

Another further useful practical guide to the drug’s usein treatment-resistant schizophrenia is a review by Pantelis & Lambert (2003).In this, the authors suggest that treatmentresistance is related to several symptom domains (Table 1) andthey offer a three-phase algorithm for the pharmacological managementof incompletely recovered (treatment-resistant) patients (Fig.1).

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Table 1 Symptom domains of schizophrenia targeted by antipsychotics (after Pantelis & Lambert, 2003)

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Fig. 1 Pharmacological management of incompletely recovered patients (after Pantelis & Lambert, 2003).

Managing clozapine-resistant patients

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Managing clozapine-resistant...

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The most comprehensive review on this topic was published byBarnes et al(1996). Again, basic factors for clozapine-resistancehighlighted in this review include comorbid drug misuse, pooradherence, inadequate duration of treatment and/or inadequatedosage. As Barnes et al note, two of these factors warrant furtherexplanation.

The first is inadequate duration of treatment. It is acceptedthat a proportion of patients have a delayed response to clozapine(Meltzer, 1992). Meltzer concluded that 30% would respond by6 weeks, a further 20% by 3 months and an additional 10–20%by 6 months. Therefore, it seems reasonable to try clozapinemonotherapy for 6 months. This leaves a residue of 30% of patientsfor whom it must be decided whether to persevere with clozapine,consider various augmentation strategies or to cease clozapinetherapy.

The second factor is inadequate dosage. Clozapine dosage canbe a relatively complicated issue. In particular, there is nomeaningful relationship between clozapine plasma levels andclinical response. However, there is a consensus in the literaturethat a plasma level of about 350–450 ng/ml has to be attainedbefore the patient is considered to be non-respondent to clozapine(Perry et al, 1991; Potkin et al, 1994).

Clozapine is also subject to considerable metabolism by thecytochrome P450 (CYP) enzyme system (Aitchison et al, 2000).There are numerous variants of the genes encoding the CYP enzymefamily within the general population, resulting in complex individualgenetic profiles and a variable response to drugs metabolisedby these enzymes (Ma et al, 2004). Therefore, in clinical practice,patients can be very susceptible to side-effects at drug doselevels that appear to be below the threshold for clinical efficacy.

Augmentation of clozapine

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Augmentation of clozapine

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A frequent treatment strategy for clozapine-resistant patientswith schizophrenia is the use of specific augmentors that aresuitable for adjunctive therapy. Clozapine is a polyvalent drugbut it lacks high-potency dopamine receptor blockade (Kerwin & Osborne, 2000).Therefore, there has been interest inusing as augmentors substituted benzamides with highly selectivedopamine receptor blocking profiles (Kerwin, 2000). Augmentationstrategies incorporating sulpiride are well documented. Theauthors of one study of sulpiride augmentation in 28 patientspartially responsive to clozapine (Shiloh et al, 1997) noteda mean reduction of about 40–50% in various clinical responsescores (Brief Psychiatric Rating Scale and Scale for the Assessmentof Positive Symptoms).

Several groups have been interested in mimicking this studywith amisulpride, a relative of sulpiride that is even moreselective at the dopamine D₂ receptor. A case series by Zink et al(2004)showed improvement in previously treatment-resistantsymptoms following a combined treatment strategy of clozapineand amisulpride. In addition, our group performed an open trialof amisulpride augmentation in a long-term (52 weeks) study.Significant improvement was observed in half of the patients,with no additional side-effects. Moreover, this study monitoredplasma levels to determine whether this was a pharmacokineticinteraction. Clozapine levels did not change throughout theduration of the trial, suggesting a pharmacodynamic interaction(Munro et al, 2004).

Augmentation with anti-epileptics
A glutamate hyperfunction hypothesis of schizophrenia has generatedinterest in the role of glutamate release inhibitors as clozapineaugmentors. In a study of 26 treatment-resistant patients receivinglamotrigine (17) or topirimate (9) in addition to their existingantipsychotic treatment (a variety of antipsychotics), a significantimprovement was observed when lamotrigine was added to risperidone,haloperidol, olanzapine or flupenthixol. However, no significanteffect was observed in patients receiving topirimate augmentationin addition to clozapine, olanzapine, haloperidol or flupenthixol(Dursun & Deakin, 2001). The therapeutic effects of lamotrigineaugmentation were also assessed in a rigorous randomised placebo-controlledcross-over study of 34 clozapine-resistant patients (Tiihonen et al, 2003).In this 14-week study, lamotrigine treatment significantlyimproved positive symptoms and general psychopathological symptoms,but had no effect on negative symptoms. The authors suggestedthat this was the first time a non-dopamine antagonist had provenefficacy in schizophrenia, giving further credence to the hyperglutamateneurotransmission hypothesis for the generation of positivesymptoms in the disorder.

Are other atypicals, alone or in combination, of use?

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Are other atypicals, alone...

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Other atypical antipsychotics were not trialled in the pre-registrationphase for their efficacy in treatment resistance. However, therehave been a number of phase IV trials that have examined thispossibility.

Risperidone
The earliest study examining the possibility that risperidonemay be of use in treatment resistance was conducted by Bondolfi et al(1998).This 8-week study of risperidone and clozapineconcluded that the two drugs are comparable. However, the studyhas been criticised for its rapid titration schedule of 1 week,which may have led to clozapine intolerance and therefore topatients receiving suboptimal doses of the drug. Later studiesinclude that by Wahlbeck et al(2000), which was a 10-week open-labeltrial of risperidone v. clozapine using a 20% decrease in Positiveand Negative Symptom Scale score as the definition of clinicalimprovement. Intention-to-treat analysis did not identify significantdifferences between the two groups, but there was an unusuallyhigh dropout rate for clozapine (5 of 10 participants), seriouslyreducing the power of the study. To date, there has been nolarge, randomised, pragmatic trial of risperidone v. clozapinethat has sufficient power to detect a difference between thetreatments.

Olanzapine
The most informative study of olanzapine in treatment resistanceis likely to be that by Conley et al(1998). This reproducedthe methodology of the pivotal Kane et al(1988) study of clozapinebut concluded that olanzapine was no better than chlorpromazinein treatment resistance. Additional studies using olanzapinefollowing treatment failures with other antipsychotics (switchingstudies) have proved disappointing. However, one (Lindenmayer et al, 2002),although showing that olanzapine was not a usefulswitch drug for general psychopathological symptoms, did demonstratean improvement in symptoms related to cognitive function. Ina further switching study, Conley et al(1999) conducted 8-weekopen and double-blind trials administering olanzapine to 44treatment-resistant patients and treating subsequent olanzapine-resistantpatients with clozapine. Only 5% of patients responded to olanzapineand, of the remaining patients who were switched to clozapine,41% responded to clozapine. The authors concluded that non-responseto olanzapine does not predict failure to respond to clozapine.Some open studies (e.g. Dursun et al, 1999) suggest that olanzapinemight be best used at higher doses in treatment-resistant schizophrenia.

Quetiapine
There is relatively little published information on controlledtrials of quetiapine v. clozapine in treatment-resistant patients,but a number of small trials and case reports suggest its usefulnessin treatment resistance (e.g. Fabre et al, 1995; Brooks, 2001).

Non-clozapine atypicals in combination
At the end of the algorithm shown in Fig. 1, many clinicianstry ad hoc combinations of atypical antipsychotics for treatmentfailures with clozapine. This usually involves a combinationof olanzapine and risperidone. There is a limited publishedevidence base on this strategy. Most publications in this areaare case reports and there are likely to be very many unpublishedcases where this strategy has been used in clinical practice.However, Lerner et al(2004) have attempted to review this scantliterature. They found little evidence other than anecdotalcase reports that augmentation of clozapine with other atypicalsproduces any benefit. Subtracting patients treated with combinationsof clozapine and another atypical leaves a very small databaseon which to draw. However, Lerner et al concluded that theremight be some benefit, which necessitates further controlledstudies.

Conclusions

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Conclusions

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Although olanzapine and risperidone are probably the most successfulantipsychotics for partially treatment-resistant patients, thereis now very little controversy about the role of clozapine inmore extreme treatment resistance. Indeed, the NICE schizophreniaguidelines of 2002 strongly recommend broader and earlier useof clozapine, suggesting that only one atypical should be triedbefore moving onto clozapine.

Most practitioners are now more concerned with managing clozapine-resistantpatients, the focus of this short review. There is reasonableevidence to suggest that augmentation strategies with sulpiride,amisulpride and lamotrigine are useful in treatment resistance,but no indication as to which patient will benefit from whichstrategy. The small proportion of patients who remain denselyresistant to any pharmacological treatment strategy should probablybe managed by a historical review of their best treatment regimeand the reinstatement of this along with psychosocial treatments.

MCQs

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MCQs

The incidence of treatment-resistant schizophrenia is:
1. 5%
2. 10%
3. 20%
4. 50%
5. 75%.
The most commonly used categoricaldefinition of treatment resistanceis :
1. prolonged hospitalisation
2. less than a 20% improvement on theBPRS
3. symptoms enduringfor more than 2 years
4. persistentnegative symptoms
5. persistentcognitive symptoms.
Definitions of treatment resistancemight also include:
1. non-adherence
2. failure of maintenance
3. comorbidity
4. aggression
5. negative symptoms.
The followingdrugs show evidence that they are specific clozapineaugmentors:
1. aripiprazole
2. ziprasidone
3. lamotrigne
4. zolepine
5. amisulpride.
The following drugs alone or in combination may be usefulforpartial treatment resistance:
1. haloperidol at low dose
2. risperidone
3. olanzapine
4. risperidoneand olanzapine
5. aripiprazole.

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MCQ answers

Footnotes

This article is the first of two in this issue in the seriesintroduced by Robin McCreadie’s editorial ‘Schizophreniarevisited’ (McCreadie, 2004). In the second, Connolly & Kelly (2005)discuss physical health and lifestyle. Previouscontributions have considered environmental influences (Leask, 2004),implementation of the NICE schizophrenia guidelines (Rowlands, 2004),cognitive deficits in first-episode schizophrenia (Gopal & Variend, 2005)and early intervention in psychosis (Singh & Fisher, 2005).

The pharmacogenetics of clozapine treatment has been discussedin a previous issue of APT: see Tsapakis et al (2004). Ed.

References and related articles

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