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Combination and augmentation strategies in treatment-resistant schizophrenia
Drug Discovery Today: Therapeutic Strategies
Vol. 8, No. 1–2 2011
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Treatment of schizophrenia
Combination and augmentation strategies in treatment-resistant schizophrenia Susanne Englisch, Mathias Zink* Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, P.O. Box 12 21 20, D-68072 Mannheim, Germany
Treatment resistance in schizophrenia puts guidelinerecommended monotherapy to a challenge, and polypharmacy is used to address treatment-refractory psychotic
features,
affective
symptoms,
cognitive
impairment, secondary obsessive–compulsive syn-
Section editors: Diana Kristensen – Department of Psychiatry, Hvidovre University Hospital, Brøndby, Copenhagen, Denmark Mikkel Myatt – Psykiatrisk Center Glostrup, Copenhagen University, Glostrup, Copenhagen, Denmark
dromes and treatment-emergent side effects caused by antipsychotics. Hereunto, both combinations of different antipsychotic agents and augmentation with mood stabilizers, antidepressants and experimental substances are applied. This review will discuss risks, benefits and levels of evidence of combination strategies involving multiple psychotropic substances, with a focus on their clinical relevance.
General considerations
Introduction Schizophrenia is among the most debilitating mental diseases, and a variety of psychotropic agents is used for its treatment. Albeit the invention of first and second generation antipsychotics (FGAs/SGAs) brought about significant improvements of both treatment outcome and quality of life for schizophrenic patients, up to 40% only experience partial remission which – aside from psychotic positive and negative symptoms – does also concern affective, cognitive and psychosocial domains. Even under ideal conditions, that is, treatment adherence, stress reduction and restraint from recreational drug abuse, *Corresponding author.: M. Zink ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
monotherapeutic treatment approaches prove insufficient in a relevant proportion of patients, which is why combination strategies are applied. Aside from multimodal nonpharmacological interventions (e.g. cognitive behavioral therapy, psychoeducation and sociotherapy), such strategies include both the ‘combination’ of equal-class substances (e.g. antipsychotics) and the ‘augmentation’ with substances of different classes (e.g. antipsychotics and mood stabilizers), both of which can be subsumed under the term ‘polypharmacy’.
DOI: 10.1016/j.ddstr.2011.09.002
While international consensus guidelines strongly recommend antipsychotic monotherapy for schizophrenia, a marked increase in both combination approaches and dose escalations have been observed lately [1]. Such proceedings not only increase treatment expenses [2], but frequently also result in off-label polypharmacy lacking adequate levels of evidence. Consequently, approximately 43% of schizophrenic outpatients receive two or more antipsychotic agents, and up to 70% are comedicated with other psychotropic drugs [3], producing ambiguous results especially with respect to tolerability aspects: a recent meta-analysis found increased mortality rates under polypharmaceutical treatment approaches in two out of four trials [4], whereas two large-scale 17
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
Scandinavian epidemiological studies did not replicate these findings [5,6]. It is still unknown whether or not polypharmaceutic strategies advance a more profound recovery, improve rehabilitative successes and diminish rehospitalization rates, raising the necessity of further randomized controlled trials (RCTs) dealing with the subject.
Data sources and search strategy Based on recent reviews [7,8], we conducted a complemental scrutiny of the online databases ‘Medline OVID’, ‘The Cochrane Library’, ‘PubMed’ and ‘scholar.google.com’ for topic-related articles published until July 2011. A screen for the terms [schizophrenia OR psychotic disorders OR psychosis] was linked with [combination OR augmentation OR addon OR addition] as well as [antipsychotic agents OR antidepressive agents OR lithium OR anticonvulsants]. Moreover, we performed an online search for ongoing subject-related studies (http://www.clinicaltrials.gov).
Overview of applied substances In addition to antipsychotic agents, schizophrenic patients receive various classes of substances: while benzodiazepines are predominantly used in the acute course of illness, antidepressants, mood stabilizers, cognitive enhancers and experimental substances are applied to treat more chronic aspects such as affective symptoms, cognitive deficits, obsessive–compulsive syndromes and treatment-emergent side effects. To address treatment-refractory positive and negative symptoms, finally, combinations of different antipsychotics are employed. Some of these approaches have evidentially proven beneficial; others, however, cannot be recommended either due to a lack of adequate evidence or a potential of side effects.
Treatment-resistant schizophrenia While there are several innovative compounds in development, clozapine is still the only evidence-based medication for treatment-refractory patients [9]. The main concerns to disfavor antipsychotic polypharmacy are the risk of cumulative side effects, pharmacokinetic interactions, a potential loss of ‘atypicity’ and rising treatment costs; yet, combined prescription is commonly practiced in treatment-resistant patients. Generally, patients with longer durations of illness, lower global functioning and high treatment adherence are more probably to be treated polypharmaceutically. The combination of FGAs with clozapine or other SGAs is common in clinical practice and follows the neurobiological rationale of enhancing the antidopaminergic receptor occupancy. This strategy, however, is not substantiated by RCTs and bears the risk of relevant extrapyramidal and other side effects. Also, differences between oral and parenteral modes of application have not yet been sufficiently evaluated. 18
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Antipsychotic combinations involving clozapine or olanzapine Clozapine and olanzapine, two SGAs with low affinity to dopaminergic receptors, but pleiotropic effects on central a1-adrenoceptors, muscarinic M1-cholinoceptors, histaminergic H1-receptors as well as 5-HT2A- and 5-HT2C-receptors, are the most common and best investigated SGAs used in combination strategies for suboptimal treatment responses in schizophrenia [10,11]. In an attempt to amplify their peculiar receptor profiles by adding a specific D2-antidopaminergic component, sulpiride and amisulpride are frequently supplemented. Sulpiride has become an established add-on strategy for insufficiently remitted psychotic symptoms [12]. While no accordingly powered trials have been performed for its analog amisulpride, its add-on has also become very common in clinical practice due to several case series, open trials as well as one small RCT [13]. Aripiprazole, a partial D2- and 5-HT1A-receptor agonist, allows for differential agonistic and antagonistic effects in the dopaminergic system, and beneficial effects in combination with clozapine on psychotic positive and negative symptoms [14,15] as well as metabolic parameters [16] have been described. The add-on of ziprasidone aims at implementing agonistic effects within the serotonergic and adrenergic systems and its successful use with clozapine has been described in numerous case reports and open trials. A head-to-head comparison of ziprasidone or risperidone combined with clozapine revealed a diverging range of side effects regarding serum prolactin, extrapyramidal symptoms and QTc-prolongation. We observed comparable impacts onto positive symptoms in treatment-resistant schizophrenia both at short and long term [17,18]. The most intensively analyzed SGA added to clozapine or olanzapine is risperidone. While previous studies showed conflicting results with regard to antipsychotic efficiency as an add-on therapeutic [7,19] treatment adherence and rehospitalization rates could be ameliorated by adding risperidone long-acting injection in clozapine-treated patients [20].
Combination strategies involving other antipsychotic agents While there are no guideline recommendations dealing with combination approaches beyond clozapine, there is some preliminary data on other SGA combinations mainly derived from observational reports. Insufficient response to risperidone treatment was tried to overcome by the add-on of amisulpride [21], which has also been successfully added in patients only partially responsive to quetiapine monotherapy [22]. Similarly, also aripiprazole was used in various combinations [23].
Affective and negative symptoms Affective dysregulation is common in the course of psychotic disorders and appears both as stand-alone depressive episodes and as part of the schizophrenic negative syndrome. Taking
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into account that up to 5% of schizophrenic patients commit suicide in their course of illness, the improvement of affective impairment is of pivotal importance, and antidepressant agents as well as mood stabilizers are applied to achieve this goal. Even though a great effort has been undertaken to improve affective symptoms in schizophrenia, meta-analyses disclosed the urgent necessity of further RCTs on the subject.
Augmentation with antidepressants Various antidepressive agents such as citalopram, duloxetine, reboxetine and venlafaxine have successfully been applied to treat intercurrent depressive symptoms in schizophrenia, and their utilization generally ranks as safe and well tolerated [24]. Furthermore, several SSRIs, trazodone and ritanserine have been reported to be of beneficial impact on schizophrenic negative symptoms [25] – a connotation that has also been linked to mirtazapine which, in addition, showed favorable effects toward neurocognitive deficits usually associated with schizophrenia in two recent RCTs [26,27], while the add-on of mirtazapine to ameliorate psychotic positive symptoms yields conflicting results to some extent. Owed to the induction of psychotic symptoms, finally, the dual dopamine and norepinephrine reuptake inhibitor bupropion has originally been prescribed with reluctance in schizophrenia. Meanwhile, however, it has been extensively studied as a smoking cessation aid in schizophrenic populations [28] and was not only able to significantly reduce nicotine consumption, but it was also associated with an amelioration of negative symptoms and antidepressive effects has in the interim successfully been applied in a small number of patients in an antidepressive indication [29].
Augmentation with mood stabilizers The term ‘mood stabilizer’ refers to a variety of substances embracing both anticonvulsants (i.e. carbamazepine, lamotrigine, pregabalin, topiramate and valproic acid) as well as lithium. Despite their limited evidence [30] concerning efficacy, safety and regulatory approval, increased prescription rates both qualitatively and quantitatively were observed in schizophrenic patients. Within the mood stabilizers, lithium is the one studied most intensely; only 11 out of 20 published trials, however, used lithium as an add-on therapeutic to antipsychotic treatment. While there was an overall improvement of treatment outcome [31], the data referring to psychotic core features in particular remain inconclusive, rendering the necessity of further RCTs. Carbamazepine was associated with an improvement of global psychopathology compared with placebo in a series of eight trials [32]; its influence on primarily psychotic features still needs to be evaluated in respectively focused studies.
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
The add-on of lamotrigine to antipsychotics in general yielded conflicting results, but seems to be effective when added to partially remitted clozapine-treated patients [33]. The GABA-analog pregabalin, which has been approved for the treatment of generalized anxiety disorder, was successfully used for the management of treatment-resistant anxious syndromes in schizophrenia [34]. While this well-tolerated approach appears encouraging, however, it lacks sufficient evidence and therefore – again – warrants the need for further evaluation. The prescription of topiramate aims at addressing different aspects of schizophrenia, and a recent naturalistic study showed it not only to improve psychopathological features but also to alleviate metabolic side effects of clozapine treatment [35]. While the substance was generally well accepted, tolerability may be limited by cognitive side effects which could significantly restrain the overall treatment outcome. Valproic acid, finally, has been able to alleviate illnessinherent aggression as well as tardive dyskinesia in several small trials; regarding the management of acute psychotic episodes, however, there was no significant difference compared with placebo when added to SGAs [36].
Experimental substances The treatment of schizophrenic deficit syndromes still posits a major challenge; hence, various experimental attempts have been exerted. Owing to the hypothesis of a partially inflammatory pathogenesis, the cyclo-ocygenase-2 (COX-2) inhibitor celecoxib has been randomly augmented in a group of amisulpride-treated, early-stage schizophrenics and showed considerably better results than placebo [37]. Another recent RCT found the phosphodiesterase-5 (PDE5) inhibitor sildenafil in chronic risperidone-treated patients superior to mere antipsychotic medication [38]. Both of these approaches, however, need to be reproduced in larger samples.
Cognitive impairment As functional outcome and rehabilitability of schizophrenic patients are determined to a great extent by their cognitive abilities, the treatment of cognitive malfunction is of pivotal importance. Yet, no gold standard has been established for the treatment of schizophrenic thought disturbances. Outside the focus of this review, nonpharmacological interventions such as specifically tailored cognitive remediation and metacognitive training have reproducibly shown moderate results, while pharmacological interventions – in accordance with different pathophysiological considerations – own predominantly experimental character.
Cholinergic system Cholinergic neurotransmission has a relevant impact on memory consolidation and is predominantly modulated by www.drugdiscoverytoday.com
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Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
muscarinic M1-receptors or the a-subunit of nicotinic cholinoceptors. The add-on of choline esterase inhibitors such as donepezil [39] and galantamine [40], however, brought about cognitive improvements no greater than placebo and therefore lacks any clinical significance. Preliminary positive results obtained with the a7-partial agonists tropisetrone or with DMXB-A need to be replicated in the future.
Glutamatergic system The glutamatergic system is known to modulate cognitive processes such as attention, working memory, executive functions and learning via the N-methyl-D-aspartate (NMDA) receptor, which is why NMDA-agonistic substances such as glycine, D-serine, D-cycloserine and sarcosine (a glycine-transporter inhibitor) have been applied to enhance cognition in schizophrenia. A recent meta-analysis embracing 26 studies and 800 schizophrenic individuals found ameliorating effects on affect regulation, schizophrenic negative and positive symptoms, cognition and general psychopathology in all of these substances with the exception of D-cycloserine [41]. Also minocycline, a tetracycline antibiotic modulating the glutamatergic system, was shown to be of beneficial impact on negative symptoms, global outcome and executive functions [42], whereas the NMDA-antagonist memantine and modulators of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors such as CX516 failed to show clinical improvement.
Dopaminergic system
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buspirone, for the 5-HT3-antagonist ondansetron and the 5-HT2A/2C-antagonist ritanserine.
Cognitive enhancers In analogy to procognitive strategies in attention-deficit hyperactivity disorder (ADHD), amphetamine analogs have been applied in schizophrenia to enhance cognition. Methylphenidate bore an elevated risk of inducing psychotic symptoms and tended to worsen verbal fluency in antipsychoticnaive schizophrenic patients and the norepinephrine reuptake inhibitor atomoxetine failed to prove efficient in schizophrenia, but a recent review on modafinil suggests an enhancement of short-term memory, attention and set-shifting abilities [44].
Experimental substances While many further substances have been experimentally applied in schizophrenia and some of them showed encouraging results, most of them lack reproduced data and require further evaluation. Sex hormones such as estradiol were beneficial in women and recently also in a subgroup of male patients [45]. Allopurinol, gingko biloba, N-acetyl cysteine (NAC), propentofylline, S-adenosyl methinonine (SAM), selegiline and warm-supplementing kidney yang (WSKY) were found helpful in well-designed small RCTs yet need verifications in larger populations [7].
Management of side effects induced by antipsychotics While the administration of antipsychotic agents is helpful and necessary to control psychotic symptoms, treatmentemergent side effects are common and narrow down treatment compliance. Careful management is necessary to counteract these frequently severe and stigmatizing symptoms.
There is convincing evidence that working memory and executive functions are modulated by dopaminergic neurotransmission. In accordance with the modified dopamine hypothesis of schizophrenia, postulating a dysfunctional dopaminergic neurotransmission within the prefrontal cortex, executive dysfunction is strongly associated with schizophrenia and dopamine agonists have been used to counterbalance such deficits: hereunto, the D1 agonist dihydrexidine, the combined D1/D2 agonist pergolide and the presynaptic D2/D3 autoreceptor agonist pramipexole have been applied, producing inconsistent results and pointing toward a genetic impact on the dopaminergic system [43]. Also the SSNRI bupropion (see ‘Augmentation with antidepressants’) showed a tendency toward improving cognitive dexterity in schizophrenia [28] but needs to be further evaluated.
Acute extrapyramidal movement disorders are common in schizophrenia treatment and correspond with the extent of D2-antidopaminergic blockade. Anticholinergic substances such as biperiden, metixen and trihexyphenidyl are successfully applied to antagonize acute dystonic movement disorders; a chronic administration, however, should be avoided due to cognitive side effects. The same applies to akathisia which predominantly occurs under FGAs but may as well appear under SGA treatment: While mirtazapine was able to alleviate akathisia, the gold standard should be the causative invention of switching to another antipsychotic.
Serotonergic system
Metabolic side effects
Cognitive performance is regulated by stimulation of 5-HT1A, 5HT2A- and 5-HT6-receptors, and modulators of the 5-HT1-4receptor subtypes have been shown to improve learning skills in men. Accordingly, promising effects have been observed in preliminary trials involving the 5-HT1A partial agonist
Weight gain is a highly relevant phenomenon under antipsychotic treatment, and clinicians struggle to manage obesity, dyslipidaemia and other metabolic derangements in schizophrenic patients. To address this matter, antipsychotic combination strategies have been applied, and the
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Movement disorders
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combination of clozapine with quetiapine ziprasidone and especially aripiprazole [16,7] allowed for relevant dose reductions of clozapine, causing significant metabolic improvements. The data regarding the potency of metformin as a monotherapeutic adjunct or in combination with sibutramine are still inconsistent, whereas the add-on of reboxetine proved helpful to manage antipsychotic-induced weight gain [46].
Sexual side effects Several mechanisms may result in sexual dysfunction in schizophrenia, among which is the elevation of serum prolactin caused by antipsychotic D2-receptor blockade. Menstrual irregularities and galactorrhea in women or gynaecomastia and sexual dysfunction in men significantly impair quality of life and are among the most common reasons for treatment incompliance. Depending on their receptor profiles, FGAs as well as SGAs with higher D2-receptor affinity are associated with an elevated risk of sexual dysfunction, and as a general guideline, the application of prolactin-sparing antipsychotics is recommended. The PDE-5 inhibitors sildenafile and vardenafile, respectively, have been successfully applied in small samples of schizophrenic patients suffering from erectile dysfunction [47]; other substances experimentally applied were bromocriptine, cabergoline, cyproheptadine, amantadine, shakuyaku-kanzo-to and selegiline which failed to show evidence for proper efficacy. Generally, little is known on the management of antipsychotic-induced sexual side effects, and due to the scarcity of data available, it is recommended that physicians rather focus on the prevention of sexual dysfunction than on its treatment.
Treatment-emergent obsessive–compulsive syndromes Obsessive–compulsive symptoms (OCS) in schizophrenia have been correlated with the administration of antiserotonergic antipsychotics in a time- and dose-dependent manner [48]. When a dose reduction of the respective antipsychotic is aspired, combination and augmentation strategies might be considered to prevent psychotic exacerbations. Preliminary data focus on OCS induced by clozapine [49]. The combination with aripiprazole or amisulpride and the augmentation with lamotrigine were able to diminish Y-BOCS scores in schizophrenia whereas the antiobsessive impact of SSRIs remains a matter of debate [50]. In general, secondary OCS in schizophrenia are a widely underestimated and unrecognized problem and require intensive further research.
Conclusions International consensus guidelines recommend monotherapeutic treatment approaches for schizophrenia; yet, polypharmacy is common in real-life clinical practice and in the focus of ongoing research (http://www.clinicaltrials.gov)
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
with eight studies currently recruiting, 12 studies still in process without further recruitment and more than 70 completed trials. The data currently available frequently lack sufficient empirical evidence; yet, some provisional conclusions seem justified and can be summarized as follows: While clozapine remains the first-line medication for treatment-refractory psychotic symptoms, complementing its receptor profile by adding SGAs with more antidopaminergic properties (e.g. sulpiride and amisulpride) may be helpful to reduce psychotic features when sufficiently long treatment at adequate dosage fails to prove efficient. The add-on of aripiprazole to both clozapine and olanzapine proved beneficial toward ameliorating metabolic side effects. The common practice of adding conventional substances to SGAs to improve their effectiveness, however, lacks empirical basis. Augmenting antipsychotic treatment regimens with antidepressants positively influenced affect dysregulation, comorbid depression and negative symptoms; the data available are still inconclusive, however, and further RCTs are required to define differential indications. Analogously, the add-on of mood stabilizers needs further assessment to evaluate their impact on both schizophrenic core features and affective symptoms. The rehabilitative outcome of schizophrenic patients depends to a critical extent on their cognitive abilities; hence, treating cognitive impairment posits a pivotal goal in the management of schizophrenia and has to date only insufficiently been addressed by psychopharmacological interventions. Several substances including antidepressants, glutamatergic, dopaminergic and serotonergic (ant-)agonists as well as cognitive enhancers and experimental substances have been applied and showed some favorable effects in single small, predominantly open-label trials. These findings, however, have in common that they lack substantiation and need to be replicated in larger populations, which is why the treatment of choice should consist of cognitive remediation in addition to sufficient antipsychotic medication. Antipsychotic side effects are common, with movement disorders, metabolic dysregulation, sexual side effects and secondary OCS being the most prominent. Anticholinergic substances are well established to manage acute dystonic movement irregularities; the treatment of choice, however, should embrace switching to a better-tolerated medication. The same applies to treatment-emergent sexual dysfunctions which are the most frequent reasons for adherence failures. Patients developing OCS secondary to the application of antiserotonergic antipsychotics may benefit from the combination with amisulpride or aripiprazole and the augmentation with lamotrigine, while the relevance of www.drugdiscoverytoday.com
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SSRIs remains a matter of debate. Metabolic derangement, finally, should be addressed by combination strategies involving metabolically more inert SGAs allowing for dose reductions of clozapine or olanzapine. The obvious prevalence of combination strategies in schizophrenia pinpoints to the fact that the currently available compounds only represent a small set of therapeutic mechanisms which turns out to be insufficient to control all aspects of illness in a relevant number of schizophrenic patients. Thus, there is an urgent need for the scientific exploration of new mechanisms and for the development and evaluation of novel substances to ease the burden of illness in schizophrenic patients.
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Funding
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This work was not supported by any funding.
Conflicts of interest M.Z. has received unrestricted scientific grants of German Research Foundation (DFG), ERAB (European Research Advisory Board), Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, further speaker and travel support from Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, Astra Zeneca, Eli-Lilly and Janssen Cilag. S.E. has received travel expenses and consultant fees from AstraZeneca, Bristol-Myers Squibb GmbH & CoKGaA, Eli-Lilly, Janssen Cilag, Lundbeck, Otsuka Pharma and Pfizer Pharma.
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Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Treatment of schizophrenia
Combination and augmentation strategies in treatment-resistant schizophrenia Susanne Englisch, Mathias Zink* Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, P.O. Box 12 21 20, D-68072 Mannheim, Germany
Treatment resistance in schizophrenia puts guidelinerecommended monotherapy to a challenge, and polypharmacy is used to address treatment-refractory psychotic
features,
affective
symptoms,
cognitive
impairment, secondary obsessive–compulsive syn-
Section editors: Diana Kristensen – Department of Psychiatry, Hvidovre University Hospital, Brøndby, Copenhagen, Denmark Mikkel Myatt – Psykiatrisk Center Glostrup, Copenhagen University, Glostrup, Copenhagen, Denmark
dromes and treatment-emergent side effects caused by antipsychotics. Hereunto, both combinations of different antipsychotic agents and augmentation with mood stabilizers, antidepressants and experimental substances are applied. This review will discuss risks, benefits and levels of evidence of combination strategies involving multiple psychotropic substances, with a focus on their clinical relevance.
General considerations
Introduction Schizophrenia is among the most debilitating mental diseases, and a variety of psychotropic agents is used for its treatment. Albeit the invention of first and second generation antipsychotics (FGAs/SGAs) brought about significant improvements of both treatment outcome and quality of life for schizophrenic patients, up to 40% only experience partial remission which – aside from psychotic positive and negative symptoms – does also concern affective, cognitive and psychosocial domains. Even under ideal conditions, that is, treatment adherence, stress reduction and restraint from recreational drug abuse, *Corresponding author.: M. Zink ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
monotherapeutic treatment approaches prove insufficient in a relevant proportion of patients, which is why combination strategies are applied. Aside from multimodal nonpharmacological interventions (e.g. cognitive behavioral therapy, psychoeducation and sociotherapy), such strategies include both the ‘combination’ of equal-class substances (e.g. antipsychotics) and the ‘augmentation’ with substances of different classes (e.g. antipsychotics and mood stabilizers), both of which can be subsumed under the term ‘polypharmacy’.
DOI: 10.1016/j.ddstr.2011.09.002
While international consensus guidelines strongly recommend antipsychotic monotherapy for schizophrenia, a marked increase in both combination approaches and dose escalations have been observed lately [1]. Such proceedings not only increase treatment expenses [2], but frequently also result in off-label polypharmacy lacking adequate levels of evidence. Consequently, approximately 43% of schizophrenic outpatients receive two or more antipsychotic agents, and up to 70% are comedicated with other psychotropic drugs [3], producing ambiguous results especially with respect to tolerability aspects: a recent meta-analysis found increased mortality rates under polypharmaceutical treatment approaches in two out of four trials [4], whereas two large-scale 17
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Scandinavian epidemiological studies did not replicate these findings [5,6]. It is still unknown whether or not polypharmaceutic strategies advance a more profound recovery, improve rehabilitative successes and diminish rehospitalization rates, raising the necessity of further randomized controlled trials (RCTs) dealing with the subject.
Data sources and search strategy Based on recent reviews [7,8], we conducted a complemental scrutiny of the online databases ‘Medline OVID’, ‘The Cochrane Library’, ‘PubMed’ and ‘scholar.google.com’ for topic-related articles published until July 2011. A screen for the terms [schizophrenia OR psychotic disorders OR psychosis] was linked with [combination OR augmentation OR addon OR addition] as well as [antipsychotic agents OR antidepressive agents OR lithium OR anticonvulsants]. Moreover, we performed an online search for ongoing subject-related studies (http://www.clinicaltrials.gov).
Overview of applied substances In addition to antipsychotic agents, schizophrenic patients receive various classes of substances: while benzodiazepines are predominantly used in the acute course of illness, antidepressants, mood stabilizers, cognitive enhancers and experimental substances are applied to treat more chronic aspects such as affective symptoms, cognitive deficits, obsessive–compulsive syndromes and treatment-emergent side effects. To address treatment-refractory positive and negative symptoms, finally, combinations of different antipsychotics are employed. Some of these approaches have evidentially proven beneficial; others, however, cannot be recommended either due to a lack of adequate evidence or a potential of side effects.
Treatment-resistant schizophrenia While there are several innovative compounds in development, clozapine is still the only evidence-based medication for treatment-refractory patients [9]. The main concerns to disfavor antipsychotic polypharmacy are the risk of cumulative side effects, pharmacokinetic interactions, a potential loss of ‘atypicity’ and rising treatment costs; yet, combined prescription is commonly practiced in treatment-resistant patients. Generally, patients with longer durations of illness, lower global functioning and high treatment adherence are more probably to be treated polypharmaceutically. The combination of FGAs with clozapine or other SGAs is common in clinical practice and follows the neurobiological rationale of enhancing the antidopaminergic receptor occupancy. This strategy, however, is not substantiated by RCTs and bears the risk of relevant extrapyramidal and other side effects. Also, differences between oral and parenteral modes of application have not yet been sufficiently evaluated. 18
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Antipsychotic combinations involving clozapine or olanzapine Clozapine and olanzapine, two SGAs with low affinity to dopaminergic receptors, but pleiotropic effects on central a1-adrenoceptors, muscarinic M1-cholinoceptors, histaminergic H1-receptors as well as 5-HT2A- and 5-HT2C-receptors, are the most common and best investigated SGAs used in combination strategies for suboptimal treatment responses in schizophrenia [10,11]. In an attempt to amplify their peculiar receptor profiles by adding a specific D2-antidopaminergic component, sulpiride and amisulpride are frequently supplemented. Sulpiride has become an established add-on strategy for insufficiently remitted psychotic symptoms [12]. While no accordingly powered trials have been performed for its analog amisulpride, its add-on has also become very common in clinical practice due to several case series, open trials as well as one small RCT [13]. Aripiprazole, a partial D2- and 5-HT1A-receptor agonist, allows for differential agonistic and antagonistic effects in the dopaminergic system, and beneficial effects in combination with clozapine on psychotic positive and negative symptoms [14,15] as well as metabolic parameters [16] have been described. The add-on of ziprasidone aims at implementing agonistic effects within the serotonergic and adrenergic systems and its successful use with clozapine has been described in numerous case reports and open trials. A head-to-head comparison of ziprasidone or risperidone combined with clozapine revealed a diverging range of side effects regarding serum prolactin, extrapyramidal symptoms and QTc-prolongation. We observed comparable impacts onto positive symptoms in treatment-resistant schizophrenia both at short and long term [17,18]. The most intensively analyzed SGA added to clozapine or olanzapine is risperidone. While previous studies showed conflicting results with regard to antipsychotic efficiency as an add-on therapeutic [7,19] treatment adherence and rehospitalization rates could be ameliorated by adding risperidone long-acting injection in clozapine-treated patients [20].
Combination strategies involving other antipsychotic agents While there are no guideline recommendations dealing with combination approaches beyond clozapine, there is some preliminary data on other SGA combinations mainly derived from observational reports. Insufficient response to risperidone treatment was tried to overcome by the add-on of amisulpride [21], which has also been successfully added in patients only partially responsive to quetiapine monotherapy [22]. Similarly, also aripiprazole was used in various combinations [23].
Affective and negative symptoms Affective dysregulation is common in the course of psychotic disorders and appears both as stand-alone depressive episodes and as part of the schizophrenic negative syndrome. Taking
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into account that up to 5% of schizophrenic patients commit suicide in their course of illness, the improvement of affective impairment is of pivotal importance, and antidepressant agents as well as mood stabilizers are applied to achieve this goal. Even though a great effort has been undertaken to improve affective symptoms in schizophrenia, meta-analyses disclosed the urgent necessity of further RCTs on the subject.
Augmentation with antidepressants Various antidepressive agents such as citalopram, duloxetine, reboxetine and venlafaxine have successfully been applied to treat intercurrent depressive symptoms in schizophrenia, and their utilization generally ranks as safe and well tolerated [24]. Furthermore, several SSRIs, trazodone and ritanserine have been reported to be of beneficial impact on schizophrenic negative symptoms [25] – a connotation that has also been linked to mirtazapine which, in addition, showed favorable effects toward neurocognitive deficits usually associated with schizophrenia in two recent RCTs [26,27], while the add-on of mirtazapine to ameliorate psychotic positive symptoms yields conflicting results to some extent. Owed to the induction of psychotic symptoms, finally, the dual dopamine and norepinephrine reuptake inhibitor bupropion has originally been prescribed with reluctance in schizophrenia. Meanwhile, however, it has been extensively studied as a smoking cessation aid in schizophrenic populations [28] and was not only able to significantly reduce nicotine consumption, but it was also associated with an amelioration of negative symptoms and antidepressive effects has in the interim successfully been applied in a small number of patients in an antidepressive indication [29].
Augmentation with mood stabilizers The term ‘mood stabilizer’ refers to a variety of substances embracing both anticonvulsants (i.e. carbamazepine, lamotrigine, pregabalin, topiramate and valproic acid) as well as lithium. Despite their limited evidence [30] concerning efficacy, safety and regulatory approval, increased prescription rates both qualitatively and quantitatively were observed in schizophrenic patients. Within the mood stabilizers, lithium is the one studied most intensely; only 11 out of 20 published trials, however, used lithium as an add-on therapeutic to antipsychotic treatment. While there was an overall improvement of treatment outcome [31], the data referring to psychotic core features in particular remain inconclusive, rendering the necessity of further RCTs. Carbamazepine was associated with an improvement of global psychopathology compared with placebo in a series of eight trials [32]; its influence on primarily psychotic features still needs to be evaluated in respectively focused studies.
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
The add-on of lamotrigine to antipsychotics in general yielded conflicting results, but seems to be effective when added to partially remitted clozapine-treated patients [33]. The GABA-analog pregabalin, which has been approved for the treatment of generalized anxiety disorder, was successfully used for the management of treatment-resistant anxious syndromes in schizophrenia [34]. While this well-tolerated approach appears encouraging, however, it lacks sufficient evidence and therefore – again – warrants the need for further evaluation. The prescription of topiramate aims at addressing different aspects of schizophrenia, and a recent naturalistic study showed it not only to improve psychopathological features but also to alleviate metabolic side effects of clozapine treatment [35]. While the substance was generally well accepted, tolerability may be limited by cognitive side effects which could significantly restrain the overall treatment outcome. Valproic acid, finally, has been able to alleviate illnessinherent aggression as well as tardive dyskinesia in several small trials; regarding the management of acute psychotic episodes, however, there was no significant difference compared with placebo when added to SGAs [36].
Experimental substances The treatment of schizophrenic deficit syndromes still posits a major challenge; hence, various experimental attempts have been exerted. Owing to the hypothesis of a partially inflammatory pathogenesis, the cyclo-ocygenase-2 (COX-2) inhibitor celecoxib has been randomly augmented in a group of amisulpride-treated, early-stage schizophrenics and showed considerably better results than placebo [37]. Another recent RCT found the phosphodiesterase-5 (PDE5) inhibitor sildenafil in chronic risperidone-treated patients superior to mere antipsychotic medication [38]. Both of these approaches, however, need to be reproduced in larger samples.
Cognitive impairment As functional outcome and rehabilitability of schizophrenic patients are determined to a great extent by their cognitive abilities, the treatment of cognitive malfunction is of pivotal importance. Yet, no gold standard has been established for the treatment of schizophrenic thought disturbances. Outside the focus of this review, nonpharmacological interventions such as specifically tailored cognitive remediation and metacognitive training have reproducibly shown moderate results, while pharmacological interventions – in accordance with different pathophysiological considerations – own predominantly experimental character.
Cholinergic system Cholinergic neurotransmission has a relevant impact on memory consolidation and is predominantly modulated by www.drugdiscoverytoday.com
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muscarinic M1-receptors or the a-subunit of nicotinic cholinoceptors. The add-on of choline esterase inhibitors such as donepezil [39] and galantamine [40], however, brought about cognitive improvements no greater than placebo and therefore lacks any clinical significance. Preliminary positive results obtained with the a7-partial agonists tropisetrone or with DMXB-A need to be replicated in the future.
Glutamatergic system The glutamatergic system is known to modulate cognitive processes such as attention, working memory, executive functions and learning via the N-methyl-D-aspartate (NMDA) receptor, which is why NMDA-agonistic substances such as glycine, D-serine, D-cycloserine and sarcosine (a glycine-transporter inhibitor) have been applied to enhance cognition in schizophrenia. A recent meta-analysis embracing 26 studies and 800 schizophrenic individuals found ameliorating effects on affect regulation, schizophrenic negative and positive symptoms, cognition and general psychopathology in all of these substances with the exception of D-cycloserine [41]. Also minocycline, a tetracycline antibiotic modulating the glutamatergic system, was shown to be of beneficial impact on negative symptoms, global outcome and executive functions [42], whereas the NMDA-antagonist memantine and modulators of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors such as CX516 failed to show clinical improvement.
Dopaminergic system
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buspirone, for the 5-HT3-antagonist ondansetron and the 5-HT2A/2C-antagonist ritanserine.
Cognitive enhancers In analogy to procognitive strategies in attention-deficit hyperactivity disorder (ADHD), amphetamine analogs have been applied in schizophrenia to enhance cognition. Methylphenidate bore an elevated risk of inducing psychotic symptoms and tended to worsen verbal fluency in antipsychoticnaive schizophrenic patients and the norepinephrine reuptake inhibitor atomoxetine failed to prove efficient in schizophrenia, but a recent review on modafinil suggests an enhancement of short-term memory, attention and set-shifting abilities [44].
Experimental substances While many further substances have been experimentally applied in schizophrenia and some of them showed encouraging results, most of them lack reproduced data and require further evaluation. Sex hormones such as estradiol were beneficial in women and recently also in a subgroup of male patients [45]. Allopurinol, gingko biloba, N-acetyl cysteine (NAC), propentofylline, S-adenosyl methinonine (SAM), selegiline and warm-supplementing kidney yang (WSKY) were found helpful in well-designed small RCTs yet need verifications in larger populations [7].
Management of side effects induced by antipsychotics While the administration of antipsychotic agents is helpful and necessary to control psychotic symptoms, treatmentemergent side effects are common and narrow down treatment compliance. Careful management is necessary to counteract these frequently severe and stigmatizing symptoms.
There is convincing evidence that working memory and executive functions are modulated by dopaminergic neurotransmission. In accordance with the modified dopamine hypothesis of schizophrenia, postulating a dysfunctional dopaminergic neurotransmission within the prefrontal cortex, executive dysfunction is strongly associated with schizophrenia and dopamine agonists have been used to counterbalance such deficits: hereunto, the D1 agonist dihydrexidine, the combined D1/D2 agonist pergolide and the presynaptic D2/D3 autoreceptor agonist pramipexole have been applied, producing inconsistent results and pointing toward a genetic impact on the dopaminergic system [43]. Also the SSNRI bupropion (see ‘Augmentation with antidepressants’) showed a tendency toward improving cognitive dexterity in schizophrenia [28] but needs to be further evaluated.
Acute extrapyramidal movement disorders are common in schizophrenia treatment and correspond with the extent of D2-antidopaminergic blockade. Anticholinergic substances such as biperiden, metixen and trihexyphenidyl are successfully applied to antagonize acute dystonic movement disorders; a chronic administration, however, should be avoided due to cognitive side effects. The same applies to akathisia which predominantly occurs under FGAs but may as well appear under SGA treatment: While mirtazapine was able to alleviate akathisia, the gold standard should be the causative invention of switching to another antipsychotic.
Serotonergic system
Metabolic side effects
Cognitive performance is regulated by stimulation of 5-HT1A, 5HT2A- and 5-HT6-receptors, and modulators of the 5-HT1-4receptor subtypes have been shown to improve learning skills in men. Accordingly, promising effects have been observed in preliminary trials involving the 5-HT1A partial agonist
Weight gain is a highly relevant phenomenon under antipsychotic treatment, and clinicians struggle to manage obesity, dyslipidaemia and other metabolic derangements in schizophrenic patients. To address this matter, antipsychotic combination strategies have been applied, and the
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combination of clozapine with quetiapine ziprasidone and especially aripiprazole [16,7] allowed for relevant dose reductions of clozapine, causing significant metabolic improvements. The data regarding the potency of metformin as a monotherapeutic adjunct or in combination with sibutramine are still inconsistent, whereas the add-on of reboxetine proved helpful to manage antipsychotic-induced weight gain [46].
Sexual side effects Several mechanisms may result in sexual dysfunction in schizophrenia, among which is the elevation of serum prolactin caused by antipsychotic D2-receptor blockade. Menstrual irregularities and galactorrhea in women or gynaecomastia and sexual dysfunction in men significantly impair quality of life and are among the most common reasons for treatment incompliance. Depending on their receptor profiles, FGAs as well as SGAs with higher D2-receptor affinity are associated with an elevated risk of sexual dysfunction, and as a general guideline, the application of prolactin-sparing antipsychotics is recommended. The PDE-5 inhibitors sildenafile and vardenafile, respectively, have been successfully applied in small samples of schizophrenic patients suffering from erectile dysfunction [47]; other substances experimentally applied were bromocriptine, cabergoline, cyproheptadine, amantadine, shakuyaku-kanzo-to and selegiline which failed to show evidence for proper efficacy. Generally, little is known on the management of antipsychotic-induced sexual side effects, and due to the scarcity of data available, it is recommended that physicians rather focus on the prevention of sexual dysfunction than on its treatment.
Treatment-emergent obsessive–compulsive syndromes Obsessive–compulsive symptoms (OCS) in schizophrenia have been correlated with the administration of antiserotonergic antipsychotics in a time- and dose-dependent manner [48]. When a dose reduction of the respective antipsychotic is aspired, combination and augmentation strategies might be considered to prevent psychotic exacerbations. Preliminary data focus on OCS induced by clozapine [49]. The combination with aripiprazole or amisulpride and the augmentation with lamotrigine were able to diminish Y-BOCS scores in schizophrenia whereas the antiobsessive impact of SSRIs remains a matter of debate [50]. In general, secondary OCS in schizophrenia are a widely underestimated and unrecognized problem and require intensive further research.
Conclusions International consensus guidelines recommend monotherapeutic treatment approaches for schizophrenia; yet, polypharmacy is common in real-life clinical practice and in the focus of ongoing research (http://www.clinicaltrials.gov)
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with eight studies currently recruiting, 12 studies still in process without further recruitment and more than 70 completed trials. The data currently available frequently lack sufficient empirical evidence; yet, some provisional conclusions seem justified and can be summarized as follows: While clozapine remains the first-line medication for treatment-refractory psychotic symptoms, complementing its receptor profile by adding SGAs with more antidopaminergic properties (e.g. sulpiride and amisulpride) may be helpful to reduce psychotic features when sufficiently long treatment at adequate dosage fails to prove efficient. The add-on of aripiprazole to both clozapine and olanzapine proved beneficial toward ameliorating metabolic side effects. The common practice of adding conventional substances to SGAs to improve their effectiveness, however, lacks empirical basis. Augmenting antipsychotic treatment regimens with antidepressants positively influenced affect dysregulation, comorbid depression and negative symptoms; the data available are still inconclusive, however, and further RCTs are required to define differential indications. Analogously, the add-on of mood stabilizers needs further assessment to evaluate their impact on both schizophrenic core features and affective symptoms. The rehabilitative outcome of schizophrenic patients depends to a critical extent on their cognitive abilities; hence, treating cognitive impairment posits a pivotal goal in the management of schizophrenia and has to date only insufficiently been addressed by psychopharmacological interventions. Several substances including antidepressants, glutamatergic, dopaminergic and serotonergic (ant-)agonists as well as cognitive enhancers and experimental substances have been applied and showed some favorable effects in single small, predominantly open-label trials. These findings, however, have in common that they lack substantiation and need to be replicated in larger populations, which is why the treatment of choice should consist of cognitive remediation in addition to sufficient antipsychotic medication. Antipsychotic side effects are common, with movement disorders, metabolic dysregulation, sexual side effects and secondary OCS being the most prominent. Anticholinergic substances are well established to manage acute dystonic movement irregularities; the treatment of choice, however, should embrace switching to a better-tolerated medication. The same applies to treatment-emergent sexual dysfunctions which are the most frequent reasons for adherence failures. Patients developing OCS secondary to the application of antiserotonergic antipsychotics may benefit from the combination with amisulpride or aripiprazole and the augmentation with lamotrigine, while the relevance of www.drugdiscoverytoday.com
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SSRIs remains a matter of debate. Metabolic derangement, finally, should be addressed by combination strategies involving metabolically more inert SGAs allowing for dose reductions of clozapine or olanzapine. The obvious prevalence of combination strategies in schizophrenia pinpoints to the fact that the currently available compounds only represent a small set of therapeutic mechanisms which turns out to be insufficient to control all aspects of illness in a relevant number of schizophrenic patients. Thus, there is an urgent need for the scientific exploration of new mechanisms and for the development and evaluation of novel substances to ease the burden of illness in schizophrenic patients.
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Funding
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This work was not supported by any funding.
Conflicts of interest M.Z. has received unrestricted scientific grants of German Research Foundation (DFG), ERAB (European Research Advisory Board), Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, further speaker and travel support from Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, Astra Zeneca, Eli-Lilly and Janssen Cilag. S.E. has received travel expenses and consultant fees from AstraZeneca, Bristol-Myers Squibb GmbH & CoKGaA, Eli-Lilly, Janssen Cilag, Lundbeck, Otsuka Pharma and Pfizer Pharma.
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