Abstract
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.
Introduction
Antipsychotic substances markedly improve therapy and prognosis for patients with schizophrenic psychoses,1 which before the advent of these compounds were considered to be severe and devastating psychiatric disorders. However, a large number of the so-called typical antipsychotic agents can cause severe extrapyramidal motoric symptoms and other side effects. 2 Moreover, up to 40% of patients with psychotic symptoms do not respond to conventional antipsychotic therapy.3 Clozapine, representing a second generation of so-called atypical antipsychotic drugs, has shown positive effects in cases of formerly treatment-resistant psychoses.4,5 However, its use is limited because of major side effects including potentially lethal agranulocytosis.6,7 Within the heterogeneous group of atypical antipsychotics, the thienobenzodiazepine derivative olanzapine has a receptor profile that is quite similar to that of clozapine, as indicated by having a greater affinity for serotonergic 5-HT2A receptors than for dopaminergic D2 receptors.8,9 The positive and negative symptoms of schizophrenic psychoses usually respond well to this drug.10,11 In contrast to clozapine, olanzapine does not induce major agranulocytosis but may, in a significant number of cases, lead to bothersome side effects including significant weight gain, sedation, anticholinergic effects and transient increases of liver enzymes.12
Faced with a partial response to antipsychotic monotherapy or because of side effects that might interfere with a patient’s compliance, clinicians often use a combination of several drugs.13,14 In particular, clozapine has been used in various combined treatment settings, as recently reviewed.15,16 Evidence for superior efficacy and tolerability exists for the combinations of clozapine with sulpiride,17 amisulpride18,19 and risperidone.20,21 Nevertheless, the widespread clinical practice of augmentation strategies stands in contrast to the scarce evidence derived in most cases from open-labelled, retrospective studies.22,23 In particular, a recent investigation compared cohorts treated with antipsychotic monotherapy or polytherapy that had, initially, not displayed differences in diagnosis, age and severity of illness scores.24 The authors reported higher cumulative doses, more side effects and a longer treatment period in the polytherapy group.
Because of positive clinical experiences regarding the combination of amisulpride and olanzapine,25 I embarked on this review with the goal of systematically evaluating reports of combinations of olanzapine with other psychotropic substances.
Methods
A systematic database search was performed of MEDLINE and BIOSIS (Ovid) using the search terms “augmentation,” “combination,” “schizophrenia,” “olanzapine,” and the names of the other substances listed in Table 126–37 and Table 2,38–45 including brand names, spanning publications from 1966 until the end of December 2004.
Published reports (n = 14) describing the combined use of olanzapine and another antipsychotic agent
Published reports (n = 8) describing the combined use of olanzapine and a non-antipsychotic agent
Results
This literature search resulted in 14 reports on the combined use of olanzapine and other antipsychotic substances. In addition, 8 reports on augmentation strategies that did not involve antipsychotic agents were retrieved. Among the publications on antipsychotic augmentation (Table 1), only 1 randomized trial was performed, regarding the combination of olanzapine and sulpiride.35 Two studies had an open prospective design,32,34 with the remaining majority characterized as case reports or retrospective chart reviews. The treatments of a total of 83 patients diagnosed with psychotic disorders such as schizophrenia or schizoaffective disorder, mostly based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), are documented (haloperidol n = 40, fluphenazine n = 1, pimozide n = 1, clozapine n = 3, risperidone n = 6, sulpiride n = 23, amisulpride n = 8, and aripiprazole n = 1). The treatment duration and monitoring varied significantly, ranging from a few days to 2 years. The daily dose of olanzapine ranged from 7.5 mg to 30 mg, with an average of 22.2 mg/d, calculated by averaging all reported doses by the combined total sample sizes. Therapeutic effects were evaluated by applying psychometric scales such as the Brief Psychiatric Rating scale (BPRS) or the Positive and Negative Syndrome scale (PANSS). However, in some cases, only clinical observations were performed to evaluate the outcome. In contrast to most of the studies, which reported favourable treatment results, the randomized trial using sulpiride35 failed to achieve a significant amelioration of psychotic symptoms; the affective state, however, improved. In addition, several case reports documented important side effects such as neutropenia27 and malignant neuroleptic syndrome as a consequence of using haloperidol as an adjuvant treatment.26 However, improvements in pre-existing side effects were reported.25 Interestingly, none of these publications evaluated the economic consequences of combined pharmacotherapy.
Because of unsatisfactory treatment responses to olanzapine, a number of non-antipsychotic substances were used as alternative add-ons (Table 2). Four of these investigations were designed as double-blind, placebo-controlled trials, 39,40,42,43 1 as a retrospective case series44 and the remaining 3 as open prospective trials. Altogether 989 patients were evaluated. Most of these patients were enrolled in augmentation studies with divalproex and valproic acid; a much smaller number were enrolled in augmentation studies with topiramate, lamotrigine, glycine, reboxetine or fluvoxamine. The monitoring period ranged from 4 weeks to 12 months, and the daily dose of olanzapine ranged from 7.3 mg to 43.3 mg, with an average of 10.8 mg/d, calculated by averaging all reported doses by the combined total sample sizes. Treatment response was assessed using psychometric scales such as BPRS, the Scale for the Assessment of Negative Symptoms (SANS) and PANSS, but never exclusively based on clinical impressions. In contrast to antipsychotic augmentations, only limited improvement on psychotic symptoms was achieved with the non-antipsychotic substances, for example, by addressing the hostility item of the PANSS rating scale. In addition, side effects of this combined therapy were absent or of minor importance. The economic consequences of this type of polypharmacy were not evaluated.
Discussion
The combination of olanzapine with other psychotropic substances is a therapeutic strategy that is used quite often in cases of treatment-resistant schizophrenic psychoses. However, because of the limited findings on augmentations with antipsychotic agents, further clinical trials are necessary to evaluate the risks and benefits.
The atypical antipsychotic substance olanzapine has been in common use in the therapy of psychiatric disorders other than schizophrenia and, more specifically, combinations with olanzapine were reported with the serotonin reuptake inhibitor (SSRI) fluoxetine in the treatment of borderline personality disorder,46 with topiramate for bipolar disorder,47 with fluoxetine for obsessive–compulsive disorder48,49 and again with the same SSRI for depression.50–53 The latter combination was additionally investigated in biological models at a molecular level.54–57
Olanzapine combinations have been prescribed to patients with treatment-resistant schizophrenic psychoses, and they are the focus of this review. Usually, treatment-resistant psychoses prompt the clinician to either switch to another monotherapy or add onto the pre-existing strategy in order to augment the pharmacological profile. In this context, it may be important to note that a recent survey detected insufficient treatment responses of positive symptoms as the main reason for applying an augmented antipsychotic therapy.58 As an alternative, switching to clozapine monotherapy would be wise, because this substance is known to be effective in formerly treatment-resistant psychoses,4,5 and more so than olanzapine.59 If clinicians prefer augmentation strategies with olanzapine, which is a substance with complex pharmacodynamic and pharmacokinetic interactions due to metabolism via the cytochrome P450 system,60,61 the importance of therapeutic drug monitoring has to be emphasized.62,63
A significant number of substances have been used in combination with olanzapine, mirroring the increased incidence of these approaches. This fact is underscored by an investigation in the United States where McCue et al counted not even 1 antipsychotic combination in a representative cohort of 454 patients in 1995. This is in contrast to 93 combinations used among 583 patients in 2001.13 Although 38 patients were treated in that sample with haloperidol and olanzapine, a solid evaluation of this specific combination was not possible because of the lack of pharmacological and clinical data. Therefore, the main clinical question remains to be answered: What benefit may be expected from these treatments in the light of risks such as malignant neuroleptic syndromes26,28 and neutropenia27 in combination therapy with haloperidol or fluphenazine or priapism in augmentation with risperidone? 33
Even the efficacy of this strategy regarding treatmentresistant positive symptoms has to be questioned: the only randomized trial, dealing with sulpiride augmentation, failed to achieve significant improvements on the PANSS scale.35 In contrast to this negative result, favourable experiences have been reported after augmentation with sulpiride,34 the closely related D2/D3-antagonistic benzamide amisulpride,25 aripiprazole37 or risperidone.32 One might be tempted to formulate the hypothesis that an additional antidopaminergic receptor interaction increases the benefits of an olanzapine-based therapy. Yet another hypothesis should be tested in the future, namely, augmentation with sulpiride35 or aripiprazole37 has resulted in improvements of negative symptoms and of depressed mood: Is it therefore possible to include an additional antidepressive component as part of therapy using antidopaminergic augmentation?
Antipsychotic augmentation ought to be compared with non-antipsychotic drugs as adjuvant therapy to olanzapine. The indication for these latter studies did not significantly differ from those for the studies of augmentation with antipsychotic agents. Only 10.8 mg of olanzapine were used in these studies, which is half of the dose applied in antipsychotic augmentations. In these latter studies, 989 patients were evaluated after augmentation with fluvoxamine, reboxetine, glycine, lamotrigine, topiramate, divalproex and valproic acid, that is, about 10 times the number of patients as compared with the antipsychotic augmentations. Moreover, these investigations followed a design of double-blind, placebo-controlled trials or at least open prospective studies and assessed the target effects with established psychometric scales. With the exception of lamotrigine and topiramate augmentation, 41 significant improvements of negative (fluvoxamine, glycine) and positive (divalproex, valproic acid) symptoms as well as side effects (reboxetine) were achieved.
A further comparison is necessary: the augmentation of clozapine with atypical antipsychotic substances16 may be considered an equally difficult topic in clinical research. Nevertheless, several double-blind placebo-controlled trials have been performed,17,20,21 and reports describing about 1300 treated patients have been published. Furthermore, the pharmacodynamic consequences of antidopaminergic augmentation of clozapine have been investigated with the tools of nuclear medicine64,65
In conclusion, this review of augmented olanzapine therapies may be of assistance in defining scientific needs but to a lesser extent in providing suggestions with regard to the clinician’s daily work, although the augmentation with valproic acid might be considered in reducing symptoms of hostility. Furthermore, the antidopaminergic augmentations with sulpiride or amisulpride follow a neurobiological rationale. However, further well-designed clinical investigations are necessary in the future. These trials can be performed, as illustrated, with antipsychotic augmentations of clozapine or non-antipsychotic augmentations of olanzapine. Optimally, they could lead to an estimation of the risks and benefits of olanzapine augmentation strategies and a ranking of the various alternatives.
Acknowledgement
Tarek Zghoul contributed to this manuscript by expert text revision.
Footnotes
Medical subject headings: antipsychotic agents; drug therapy, combination; olanzapine; schizophrenia.
Competing interests: Dr. Zink has received speaker fees from Pfizer.
- Received March 31, 2005.
- Accepted August 11, 2005.
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