Case studies of adjunctive agents in clozapine-resistant schizophrenic patients

Approximately 40%-70% of neuroleptic-resistant schizophrenic patients are nonresponders even to clozapine. Several clozapine augmentation strategies have come into clinical practice, although often without evidence-based support. This study aims to critically review all the reported case studies regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. All published case studies examining the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic patients were searched for in the MEDLINE database from January 1980 to February 2004. Case studies regarding ECT as a clozapine augmentation strategy were not included in our study. All the included papers were critically reviewed and examined against a set of clinical and pharmacological parameters, outcome measures, and reported side effects. Fifteen case studies regarding the efficacy and safety of sulpiride, risperidone, olanzapine, lithium, lamotrigine, fluvoxamine, and bromocriptine as clozapine adjuncts were found. A total of 33 schizophrenic or schizoaffective patients were included. Of the 15 studies, 8 were associated with risperidone. The duration and dosage of previous clozapine monotherapy was adequate for 16 patients. Plasma clozapine level was assessed for only 7 patients. Outcome measures were used for only 11 patients. The outcome was positive in 13 studies. Combined treatments were generally well tolerated, and side effects never resulted in discontinuation of treatment. Most case studies favor the use of risperidone as an adjunctive agent in clozapine-resistant schizophrenic or schizoaffective patients. However, small numbers of patients and other methodological shortcomings limit the impact of evidence provided.     

Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia

BACKGROUND: Approximately 40% to 70% of neuroleptic-resistant schizophrenic patients are nonresponders to clozapine. Several clozapine augmentation strategies have come into clinical practice although often without evidence-based support. Among these strategies, the combined use of clozapine with another antipsychotic has been reported for up to 35% of patients receiving clozapine. OBJECTIVE: The purposes of the present work were to (1) review the available literature on the efficacy and safety of the clozapine augmentation with another antipsychotic using a MEDLINE search of the literature from 1978 to December 2005 and (2) to propose an operational definition of schizophrenia refractory to clozapine ("ultraresistant schizophrenia") for the implementation and homogenization of future therapeutic trials. CONCLUSION: Case controls and open clinical trials largely dominate the literature, and there are only 4 double-blind studies of clozapine augmentation with antipsychotics. The results of these studies are somewhat discrepant. Moreover, the heterogeneity of definitions of resistance to clozapine, of outcome measures and of dose and duration of pharmacological trials is a major limitation for drawing conclusions.     

Clozapine augmentation with long-acting antipsychotic injections: A case series and systematic review

Background

Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality.

Methods

Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales.

Results

Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported.

Conclusion

This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.     

Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review.

Approximately 40-70% of treatment-resistant schizophrenic patients fail to benefit from clozapine monotherapy or are partial responders. During the last years several clozapine adjunctive agents have come into clinical practice. This study aims to critically review all published randomized, double-blind, placebo-controlled clinical trials (RCTs) regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. A MEDLINE search for RCTs on clozapine adjunctive agents published from January 1980 to February 2004 was conducted. All identified papers were critically reviewed and examined against several methodological features as well as clinical and pharmacological parameters. Eleven trials including 270 patients, partial or non-responders to clozapine, assessed the efficacy of sulpiride, lithium, lamotrigine, fluoxetine, glycine, d-serine, d-cycloserine and ethyl-eicosapentanoate (E-EPA) as clozapine adjuncts. There were eight parallel-group and three crossover trials. The inclusion criteria varied widely. The duration as well as the dosage of clozapine monotherapy were reported adequate in only one trial. Plasma clozapine levels were assessed in only three trials. Main side-effects reported were hypersalivation, sedation, diarrhea, nausea, hyperprolactinaemia. The outcome favored clozapine augmentation with sulpiride, lamotrigine and E-EPA. Lithium was shown to benefit only schizoaffective patients. However, the methodological shortcomings of trials analyzed limit the impact of evidence provided.     

When symptoms persist: clozapine augmentation strategies

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.     

Somatic augmentation strategies in clozapine resistance--what facts?

BACKGROUND: Polypharmacy without evidence-based support is sometimes needed for patients treated with 40% to 70% clozapine who are clozapine nonresponders. Several somatic augmentation strategies are proposed in the scientific literature, with different levels of evidence for safety and efficacy. OBJECTIVES: The purpose of the present study is to review the available literature on the efficacy and safety of clozapine augmentation with somatic agents other than antipsychotics. The following classes of agents are considered: (1) mood stabilizers, (2) antidepressants, (3) electroconvulsive therapy and repetitive transcranial magnetic stimulation, (4) glutamatergic agents, (5)fatty acids supplements, and (6) benzodiazepines. RESULTS: Case controls and small-size clinical trials largely dominate the literature, limiting the power to draw conclusions concerning safety issues and the meaning of negative studies. Moreover, variable definitions of clozapine resistance, heterogeneous outcome measures, and short duration of treatment trials are additional limitations. CONCLUSION: Generally, adjunctive strategies for clozapine-resistant patients remain based on scarce evidence of efficacy and significant safety concerns. Low-frequency repetitive transcranial magnetic stimulation, fatty acids supplements, and mirtazapine showed good tolerability and some efficacy, but the results need replication.     

Are atypical antipsychotic drugs also atypical antidepressants?

OBJECTIVE: To report a case series and review the psychopharmacology of the neuroleptic drugs to suggest that the atypical antipsychotic drugs may have an antidepressant action, at least for those patients with the melancholic subtype. METHOD: We note the literature suggesting that the older (or typical) antipsychotic drugs were established as having antidepressant activity, describe an open study of some two dozen patients with a treatment-resistant melancholic depression, describe rapid resolution of depression and augmentation benefits associated with commencing an atypical antipsychotic drug in a percentage of subjects, and then review relevant psychopharmacological studies to consider whether there is a rationale for use of antipsychotic drugs to treat depression. RESULTS: Of some two dozen patients treated with an atypical antipsychotic drug, almost immediate improvement was noted in four patients, and evidence of augmentation benefit obtained in another three patients. CONCLUSIONS: Impressions from this case series are encouraging. However, as open clinical observational studies are problematic, controlled studies are required to establish whether the atypical antipsychotic drugs have a role in the management of certain expressions of depression, and, in particular, treatment-resistant melancholic depression.     

Augmentation of clozapine with a second antipsychotic – a meta‐analysis of randomized,placebo‐controlled studies

Objective: Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment. Method: Meta‐analysis of randomized, placebo‐controlled studies of antipsychotic augmentation of clozapine treatment. Results: Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) ?0.180, 95% CI ?0.356 to ?0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679–2.345) or on CGI scores (effect size ?0.661, 95% CI ?1.475 to 0.151). Duration of study was not associated with outcome (P = 0.95). There was no evidence of publication bias. Conclusion: In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co‐therapy with clozapine.     

Augmentation of olanzapine in treatment-resistant schizophrenia

OBJECTIVE: Up to 40% of patients with schizophrenic psychoses have symptoms that are resistant to monotherapy with antipsychotic drugs. In consequence, combinations of drugs are often used, especially based on the antipsychotic agents clozapine and olanzapine because of their broad receptor-interaction profile. The aim of this review was to provide a critical overview of the published results of olanzapine augmentation. METHODS: A systematic database search was performed of MEDLINE and BIOSIS (Ovid), looking for publications on augmented therapeutic approaches involving olanzapine. The search terms used were "augmentation," "combination," "schizophrenia," "olanzapine," and the names of other antipsychotic drugs and non-antipsychotic agents, including brand names, spanning publications from 1966 until the end of December 2004. RESULTS: Of 14 reports dealing with 8 different antipsychotic augmentation strategies (83 patients), only 1 trial, of sulpiride-olanzapine therapy, was performed in a randomized manner. Based on clinical observation, a significant number of the treatments led to favourable results. In contrast to adjuvant therapy with antipsychotic drugs, augmentation of olanzapine with glycine, antidepressants or mood stabilizers was evaluated in well-designed clinical trials (8 publications, 989 patients), with distinct improvements of positive and/or negative symptoms reported. CONCLUSIONS: The combination of olanzapine with antidopaminergic atypical antipsychotic agents seems to follow a neurobiological rationale. The augmentation trials with non-antipsychotic agents, for example, mood stabilizers, were successful and showed that randomized and placebo-controlled trials are feasible. Therefore, systematic evaluations of antipsychotic agents as adjuvant therapy are possible as well as necessary to determine the benefits and risks of any new treatment strategy.     

Effects of sertindole on cognition in clozapine-treated schizophrenia patients

Nielsen RE, Levander S, Thode D, Nielsen J. Effects of sertindole on cognition in clozapine‐treated schizophrenia patients. Objective: To assess the cognitive effects of sertindole augmentation in clozapine‐treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial. Method: A 12‐week, double‐blinded, randomized, placebo‐controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of sertindole or placebo as adjunctive treatment to clozapine. Results: Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF‐F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF‐F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations. Conclusion: The clozapine‐treated patients displayed marked cognitive deficits at baseline. Adding sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.     

Treatment Refractory Schizophrenia

Treatment resistance constitutes a significant dilemma in schizophrenia since it affects a substantial number of patients, their families and the health care professionals involved in their care. Nonresponsiveness needs to be approached as a multidimensional syndrome by specifying which symptoms in the spectrum of positive symptoms, negative symptoms, excitement/hostility, cognitive symptoms, and anxiety/depression are failing to respond to treatment. This review presents some of the clinical, demographic and biological correlates of nonresponse, in addition to compliance issues, psychosocial factors or side effects and as-yet-untreated comorbidities as a source for nonresponse. The effects of the atypicals clozapine, olanzapine, risperidone and quetiapine as compared to typicals are reviewed using available double-blind studies in this treatment refractory group of schizophrenia patients. The limited number of reports on the comparison of atypical compounds amongst each other are critically presented. Given that a subset of patients still do not respond to these agents, clinicians are using various augmentation strategies. We review studies with augmentation strategies which remain difficult to interpret given the open label and uncontrolled nature of most of these studies.     

The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study

Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results, the present 24-week double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 200 mg/day of lamotrigine or a placebo. A final sample of fifty-one patients completed the study. The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative, positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.     

Management of marked liver enzyme increase during clozapine treatment: a case report and review of the literature

OBJECTIVE: Clozapine-induced hepatotoxicity is not infrequent and usually transient. It mostly causes asymptomatic elevation of liver transaminases. "Elevation in liver enzymes to what extent should preclude further treatment?" or "Is only a dose-reduction sufficient?" are questions yet to be answered. The present article uses a case report to discuss the treatment alternatives when liver enzymes reach three times the upper normal limits during the clozapine therapy. METHODS: In the following case report, the authors describe a 27-year-old male patient diagnosed with schizophrenia, resistant to different atypical and typical antipsychotics. Based on the pathological findings of our patient and a review of the literature, the author summarizes the reasons for the liver enzymes increase and treatment alternatives during clozapine treatment. RESULTS: Substantial improvement was achieved with clozapine therapy. Increase in liver enzymes at the beginning of the clozapine treatment was successfully managed with a multidisciplinary approach: the treatment was initially withdrawn, afterwards restarted, and carefully continued. CONCLUSION: The authors demonstrate that clozapine may be cautiously continued in selected patients who showed marked psychiatric improvement with clozapine in the face of liver enzyme elevation.     

Clozapine withdrawal. A review

The article describes the symptoms of withdrawal of clozapine and their possible causes as well as research on switching from clozapine to another antipsychotic drug. A computerised search was conducted using MEDLINE (1966-1997) to retrieve reports of clozapine withdrawal. Fifteen case reports and sixteen withdrawal studies (only one of them double-blind and two single-blind) were identified. Clozapine multi-receptors profile seems to be responsible for withdrawal symptoms--several specific mechanisms are suggested: cholinergic supersensitivity, dopaminergic supersensivity, special role of D4 receptors, possibilities of serotonergic, noradrenergic and GABA-ergic involvement. Risk of relapse after withdrawal of clozapine seems to be greater than after withdrawal of classical neuroleptics. Some patients might become de novo neuroleptic resistant for at least several weeks after withdrawal. Therefore, clozapine should be stopped only due to strong clinical indications, and if only possible, the withdrawal should be slow (50 mg/week). To prevent relapse of psychosis some experts advocate starting new antipsychotic drugs in therapeutic dosage before withdrawal of clozapine is completed. In case of emergency, when clozapine (high dosage) must be withdrawn immediately, patient must be hospitalised and cholinergics might be considered to prevent, cholinergic rebound". There are no established guidelines which antipsychotic to choose after withdrawal of clozapine. In general, classical antipsychotics are ineffective. Thioridazine is suggested because of its prominent anticholinergic activity, but there is no clinical evidence of advantage of this treatment in comparison to classical drugs. Risperidon and especially olanzapine are promising possibilities, but initial data are disappointing. Benzamides might be another possibility but clinical data are scarce. These important issues require further studies.     

Optimal dosing of atypical antipsychotics in adults: a review of the current evidence

This review describes dosing strategies used to optimize the beneficial effects of atypical antipsychotic medications. Differences between manufacturers' recommended dosing and actual clinical practice are reconciled using evidence from pivotal double-blind randomized registration studies, other randomized clinical trials, case series, and case reports. With clozapine and perhaps olanzapine, plasma levels are correlated with therapeutic response; with risperidone, plasma levels are not correlated with therapeutic response but may be related to the occurrence of extrapyramidal symptoms. Information related to optimal dosing of quetiapine and ziprasidone is more limited. In clinical practice, the mean daily dose of risperidone has decreased, whereas that for olanzapine is increasing. The percentage of patients receiving quetiapine at doses above the manufacturer's recommended maximum is higher than would be expected, further illustrating that dosing ranges established during registration studies may not reflect the needs of day-to-day practice.     

Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment

BackgroundSeveral placebo controlled studies investigating lamotrigine augmentation of clozapine in schizophrenia patients with partial response have shown varying results. The aim of this study was to further investigate the efficacy and safety of this augmentation strategy, and its effect on the glutamatergic system through utilizing mismatch negativity (MMN) component of auditory event related potentials.MethodsThe study was designed to evaluate the efficacy and safety of lamotrigine augmentation of clozapine in a 12-week, double-blind, placebo-controlled, prospective, randomized design. Thirty-four patients diagnosed according to DSM-IV schizophrenia criteria and with partial response to clozapine were included. Patients were randomized to 25 mg/day of lamotrigine or placebo, gradually increasing up to 200 mg/day on the 6th week. The change in psychopathology was assessed with Positive and Negative Syndrome (PANSS), Calgary Depression (CDS) and Clinical Global Impression-Severity (CGI-S) scales. A neuropsychological test battery was administered and MMN measurements were also obtained at baseline and endpoint. Safety evaluation included physical examination, UKU Side Effect Rating Scale (UKU) assessment and serum drug level measurements.ResultsNo significant differences were found between the two treatment groups in PANSS Positive and General Psychopathology, CDS, neurocognitive test and UKU scores, as well as MMN measurements. PANSS Total, Negative and CGI-S scores showed significant improvement compared to lamotrigine in the placebo group.ConclusionThis study did not show any benefit of augmentation of clozapine with lamotrigine in schizophrenia patients with partial response. The need for further investigation of other augmentation strategies of clozapine in partially responsive schizophrenia patients is evident.     

Leponex, 10 years after -- a clinical review

Clozapine was one of the major advances in the treatment of schizophrenia since the introduction of the classic antipsychotic agent chlorpromazine in the 1950s. Over the past 10 years, clozapine has become the reference compound for the development of new antipsychotics, and new drugs have been developed which have also claimed atypical status. The indications of clozapine were recently extended to Psychosis in Parkinson's disease and harmonized in the European Union. This provides the opportunity to update the data on clozapine in the treatment of schizophrenia. In this article we review current clinical evidence in schizophrenia to address the following issues: 1) Efficacy in refractory/positive symptoms: a systematic and critical analysis of 14 double-blind clinical trials in comparison with both standard and novel antipsychotics show consistent findings in favour of clozapine, with all but three of the reports demonstrating superiority. The review of studies allow us to say little about the predictors of treatment response, time to clozapine response and about the impact of clozapine on the quality of patients'life and longer-term outcome. Treatment options for clozapine non-responders are reviewed. 2) Risk of EPS: clozapine is considered to have a minimal risk of EPS and in all studies where a valid methodology was used, a clear superiority over the other neuroleptics is demonstrated. It is pointed out that, if the prevalence and incidence of EPS with clozapine is low, it is not zero. All the studies assessing clozapine treatment for TD have major methodological limitations, so no final conclusion can be drawn. 3) Efficacy for primary and secondary negative symptoms and neurocognitive effects: the data of clinical studies where negative symptoms scales were used favour clozapine in terms of improvement. However most of the studies were carried out in populations with predominantly positive symptoms. With regard to the need to distinguish primary and secondary symptoms, data are conflicting regarding the benefit of clozapine. Due to the lack of studies with a valid methodology, no definitive conclusion can be drawn about the efficacy on clozapine on the deficit syndrome and on neurocognitive disorders. 4) Impact on suicide risk: 4 out of 6 retrospective studies provide evidence for the ability of clozapine therapy to reduce suicidal behaviour. The results of a recent randomized, parallel-group study designed to compare clozapine versus olanzapine in preventing suicide attempts seems to confirm this hypothesis. We also address the tolerability and safety data, especially haematologic, comitial, cardiovascular and metabolic side-effects. The effectiveness of blood monitoring for the management of neutropenia and agranulocytosis demands that the recommendations are strictly followed. The use of clozapine at doses higher than 600 mg daily should follow published recommendations, in order to minimize the risk of seizures; these include anticonvulsant regimens based on blood levels. With regard to the cardiovascular mortality, if clozapine therapy has negligible effects on QT interval, its association with potential fatal myocarditis cannot be excluded in young patients who should be investigated if they develop cardiac symptoms in the first weeks of treatment. Available data support the notion that the frequency of bodyweight gain is high with several new antipsychotics, including clozapine. Potential long term effects of bodyweight gain on mortality and morbidity have to be taken into consideration. The pharmacological mechanisms underlying the "unique clozapine profile" is discussed. Clozapine remains the only antipsychotic with efficacy at relatively low D2 receptor occupancy. The pharmacogenetic and pharmacokinetic aspects are also reviewed. Finally, the place of clozapine in the current treatment of schizophrenia is highlighted to inform the development of guidelines for clinical management.     

Clozapine-resistant schizophrenia related to an increased metabolism and benefit of fluvoxamine: four case reports

OBJECTIVE: Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them. BACKGROUND: Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders. CASE-REPORTS: We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold. CONCLUSION: Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.     

Clozapine augmentation: safety and efficacy

While clozapine has been demonstrated to be efficacious in refractory schizophrenia and possibly schizoaffective as well as bipolar disorders, a substantial number of patients still remain unresponsive. One strategy in treating these refractory patients is to augment clozapine with other somatic treatments. This article reviews the efficacy and safety of the combination of clozapine with other somatic treatments. A total of 70 articles were obtained from a manual, as well as computerized (Medline), search of the English language literature from 1978 to March 1998. Few controlled studies exist; most were case reports/series. From these data, the greatest risk of adverse effects seems to be associated with clozapine combined with benzodiazepines, valproate, or lithium, but no currently evaluated combination is absolutely unsafe. In terms of efficacy, the data suggest a number of potential augmentation strategies, although controlled data are few. Combination therapies with clozapine are common in clinical practice, despite a lack of empirical data, and the benefits and risks of these combinations need to be systematically reviewed.