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Review
Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy Expert Rev. Neurother. 14(1), 67–73 (2014)
Peter J McKenna*1 and Ann M Mortimer2 1
FIDMAG, Germanes Hospitala`ries, and CIBERSAM, C/. Dr. Antoni Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain 2 The Eleanor Centre, 21 Eleanor Street, GRIMSBY, North East Lincolnshire, DN32 9EA, UK *Author for correspondence: [email protected]
In 60 years of use of antipsychotic drugs in schizophrenia, the only definite advance has been the introduction of clozapine. Some but not all other atypical or second-generation drugs may have small therapeutic advantages over conventional antipsychotics, but this remains controversial. New entrant atypicals seem unlikely to be therapeutically superior to conventional drugs, and glutamatergic drugs have yet to fulfill their theoretical promise. There is considerable current interest in novel mechanisms of antipsychotic action, but no such drugs have yet reached market authorization. A psychotherapeutic intervention, cognitive behavioral therapy has also found a place in the treatment of schizophrenia. However, the size of its effect against psychotic symptoms is small, and current evidence suggests no effect against negative symptoms or in reducing relapse. KEYWORDS: antipsychotic • cognitive behavioral therapy • dopamine • glutamate • mechanism of action • schizophrenia
Schizophrenia continues to present one of the greatest therapeutic challenges in psychiatry. For decades after its identification by Kraepelin and Bleuler, it was essentially an untreatable disorder, notwithstanding the sometimes enthusiastic use of measures up to and including frontal lobotomy. The serendipitous discovery of chlorpromazine in 1952 marked the beginning of the modern era of psychopharmacological treatment, which subsequently saw the introduction of over 30 further dopamine D2 receptor blocking antipsychotic drugs. However, the limitations of this form of treatment soon became apparent, and today it is accepted that conventional drugs are not curative in most cases, and that between 5 and 25% of schizophrenic patients are resistant to treatment [1]. Two developments have changed the therapeutic landscape in schizophrenia. The first was the worldwide introduction of clozapine in the early 1990s, following the demonstration by Kane and co-workers [2] that it was superior to chlorpromazine in treatmentresistant patients. This, coupled with the recognition that it did not produce Parkinsonism www.expert-reviews.com
10.1586/14737175.2014.864237
and tardive dyskinesia, led to the now widely accepted view that clozapine is the first significant therapeutic advance in schizophrenia since the introduction of chlorpromazine. It has also led to a search for other similar drugs, which might show greater effectiveness and/or less extrapyramidal side-effects. As a result, there are now around 12 so-called atypical or second generation antipsychotics currently in use, and more are under development. Whether some of these show superior effectiveness to conventional or first-generation antipsychotics drugs is currently the subject of intense debate. The second development has been the rise of psychological treatments in schizophrenia, in particular cognitive behavioral therapy (cognitive therapy, CBT). The pioneering study here was by Kuipers et al. [3], who found CBT to be effective compared with treatment as usual in a sample of 60 schizophrenic patients with at least one positive psychotic symptom resistant to drug treatment. More than 30 subsequent trials of CBT, large and small, have since been carried out, and have had quite varied findings. Nevertheless, based on support from meta-analysis, CBT has been
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recommended by the highly respected UK National Institute of Clinical Excellence (NICE, [4,5]), as well as by other guideline development groups around the world [6]. In this article, we provide an update of the current status of atypical antipsychotics, briefly review some important criticisms and outline possible future developments in the field. We also review the state of the evidence concerning CBT for schizophrenia, note ways in which the therapy is being extended and highlight some of the challenges it faces. Atypical & novel antipsychotic drugs Current status
A comprehensive meta-analysis of atypical versus conventional antipsychotics was carried out by Leucht et al. [7] in 2009. They found a pooled effect size of -0.52 (CI: -0.29 to -0.75; 23 studies) for clozapine on overall symptom scores, -0.31 (-0.19 to -0.44; 13 studies) for amisulpride, -0.28 (-0.18 to -0.38; 28 studies) for olanzapine and -0.13 (-0.05 to -0.22; 34 studies) for risperidone (the negative sign favors the atypical). As the confidence intervals indicate, these effect sizes were all significant, but apart from for clozapine they all fell into the ‘small’ range. Five more atypicals, aripiprazole, quetiapine, sertindole, ziprasidone and zotepine showed no significant advantage over conventional drugs. Leucht et al. [7] concluded that the superior effectiveness of clozapine was supported, and that there were smaller advantages for some but not all atypicals. While Leucht et al.’s [7] conclusions with respect to clozapine are uncontroversial, there are at least three threats to the acceptance of the finding that some other atypicals are also superior to conventional drugs. One is a longstanding but still topical argument that the apparent therapeutic superiority of these drugs simply reflects the high doses – and consequent decreased tolerability – of the typical antipsychotics used as comparators in some of the trials [8]. Thus in a meta-analysis published in 2000, Geddes et al. [9] found that an observed advantage in favor of atypical drugs become smaller as the mean dose of haloperidol or chlorpromazine used in the trials increased. Three years later, Davis et al. [10] explored the effect of comparator dose in depth in a meta-analysis that included a larger set of studies. The results of several different analyses led them to conclude that there was no significant effect of haloperidol dose on the advantage of atypical over conventional drugs. Leucht et al. [7] also examined the effect of comparator dose in their meta-analysis; once again no moderating effect was found. The second challenge is that two further recent meta-analyses, carried out on behalf of official guideline development groups in England and Canada, have failed to find clear evidence of therapeutic superiority for any atypical antipsychotics other than clozapine [5], or for all atypicals including clozapine [11]. However, it should be noted that both these meta-analyses departed somewhat from the conventional approach of pooling data from as many different sources as possible, and instead opted for a large series of smaller metaanalyses, which compared atypicals with either chlorpromazine or haloperidol, and/or which divided studies according to 68
whether the BPRS or the PANSS was used to rate symptoms and/or whether the studies were short-, medium- or long-term, and so on. At the very least, such a ‘splitting’ as opposed to ‘lumping’ approach will reduce the power of meta-analysis to detect differences between atypical and conventional antipsychotics. The failure of one of these meta-analyses to support the therapeutic superiority of clozapine [11] also lacks credibility. Perhaps the most important cautionary note is sounded by two recent, large ‘pragmatic’ trials of atypical antipsychotics. The first of these, the CATIE study [12], randomly assigned just under 1500 schizophenic patients to treatment with olanzapine, quetiapine or risperidone, or to a conventional drug, perphenazine. (A ziprasidone arm was also later added after this drug was approved for clinical used in the USA). Patients were followed under double-blind conditions for up to 18 months, with the main outcome measure being time to discontinuation of treatment. It was found that neither time to the discontinuation of treatment for any cause nor time to the discontinuation for lack of efficacy was significantly longer for quetiapine, risperidone or ziprasidone than for perphenazine; there was a significant advantage for olanzapine on both measures, but this did not survive controlling for multiple comparisons. Symptom outcomes were not examined statistically, but the authors noted that, while olanzapine produced greater reductions in scores compared with perphenazine, this was counterbalanced by smaller changes with the other atypicals. Results were similar in the CUtLASS study, an open trial, which examined 227 patients with schizophrenia whose medication was changed because of inadequate response or adverse effects [13]. The patients were randomized to either conventional or atypical treatment (not including clozapine), with the choice of individual drug being made by the treating psychiatrist. No significant advantage was found for any atypical in terms of quality of life, symptoms or associated costs of care. The findings of these trials are open to interpretation. Lieberman [14], the leader of the CATIE trial, concluded: ‘The numerous antipsychotic drugs, however they might be classified, are more similar to than different from each other. To the extent that antipsychotics differ, it is more in their side effects than therapeutic effects.’ Leucht [15], in contrast, argued that the differences between the findings of his meta-analysis and those of the CATIE study were more apparent than real. He noted that olanzapine was found to be superior on several efficacy outcomes in CATIE (drop-out due to inefficacy, time on effective treatment), and that the poor performance of risperidone in this trial could have been due to the fact that the modal dose was 3.9 mg/day, meaning that many patients would have received only 1.5 or 3 mg mg/day (guidelines suggest 2–8 mg/day). Several new entrant atypical drugs have appeared in the past few years, including iloperidone [16], blonanserin [17], asenapine [18] and lurisidone [19]. None of them have been found to be more effective than conventional antipsychotics. At the same time, they have not been found to be Expert Rev. Neurother. 14(1), (2014)
Current & future treatment modalities in schizophrenia
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significantly inferior to other atypicals such as olanzapine or risperidone. However, because the therapeutic advantage of these latter drugs is small, the sample sizes to convincingly demonstrate non-inferiority will need to be large. In fact, in the studies to date there are indications of numerically lower reductions in symptom scores compared with the comparator atypical, suggesting that these new drugs will ultimately not fall into the ‘slightly better than conventionals’ subcategory, if such a subcategory exists. Future prospects & challenges Dopamine receptor antagonists
The majority of ‘pipeline’ antipsychotic drugs have dopamine and other receptor affinity profiles that are not greatly different from existing drugs. Even so, it may be possible to design new drugs with combinations of affinities that avoid those known to be associated with side-effects. For instance, the combination of the ‘structural scaffolds’ of dopamine and serotonin has produced a group of azecine derivatives, which are effective in animal models of psychosis but manifest substantially better tolerability than both haloperidol and risperidone [20]. Cariprazine is a novel D3 preferring, dopamine receptor partial agonist in Phase III clinical development for the treatment of schizophrenia and bipolar mania [21]. It remains to be seen whether it affords any efficacy advantages over existing antipsychotic drugs. Nevertheless, cariprazine’s active metabolite, didesmethyl cariprazine, has a half life of 2–3 weeks, which could lead to it having potential as a once weekly oral dose formulation, something that is lacking (and arguably very much needed) in the current therapeutic armamentarium. l-stepholidine (l-SPD), a plant derived alkaloid, is a D1/ 5-HT1A agonist and a D2 antagonist. Preliminary clinical trials suggest that it improves both positive and negative symptoms, without producing significant extrapyramidal side effects [22]. Dimerization of dopamine D2 receptors is a phenomenon observed in post-mortem schizophrenia brain tissue and in experimental animals challenged with amphetamine. It is thought that the dimerized receptor complex interferes with dopamine transporter mechanisms. This may represent a promising new target for antipsychotic action in the future. Glutamatergic drugs
As a neurochemical theory of schizophrenia, the glutamate hypothesis – based on the finding that glutamate antagonists like phencyclidine and ketamine induce a psychotic state that is arguably more similar to schizophrenia than that produced by amphetamine – remains highly influential [23]. The road to glutamate-based drug treatments, however, has proved rather more rocky. Initial trials of drugs with indirect glutamate agonist actions at NMDA and/or other ionotropic glutamate receptors provided evidence for a therapeutic effect on negative, but not positive, symptoms [24]. (Direct glutamate agonists are too rapidly metabolized to be useful, and also have the potential to cause neuronal damage through excitotoxic actions.) A subsequent large trial of glycine and cycloserine in www.expert-reviews.com
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171 schizophrenic patients with persistent negative symptoms, however, failed to find evidence of significant superiority for either drug over placebo [25]. Nor did Lieberman et al. [26] find any therapeutic effect of memantine, a non-competitive antagonist at the NMDA receptor, in a placebo-controlled trial of 138 patients. A last minute reprieve for indirect glutamate agonists is not completely ruled out. Thus, a recent meta-analysis, which included both the above large negative trials [27] found evidence of small-to-moderate effectiveness against all classes of schizophrenic symptom. Even so, none of these compounds is currently the subject of trials activity. Another possible way of remediating the putative glutamatergic deficit in schizophrenia is to target metabotropic glutamate receptors. The drug LY2140023 (also known as pomaglutamed methionil), a direct agonist at this receptor, has been the subject of two published clinical trials. In the first, it was found to be almost as effective as olanzapine [28]. In the second there was a marked placebo response, from which neither olanzapine nor LY2140023 separated [29]. Lilly, the developers of the drug, have recently announced that a third trial found no superiority against placebo, and have halted further development [101]. The peptide transmitter N-acetylaspartylglutamate (NAAG) is an agonist at the metabotropic glutamate receptor, mGluR3 and is inactivated by glutamate carboxypeptidase II (GCPII). Some NAAG peptidase inhibitors such as the drugs ZJ43 and (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA) are not only effective in glutamatergic animal models of psychosis, but also block the effects of amphetamineinduced motor activity [30]. Glycine transporter 1 (GlyT1) inhibition preserves synaptic glycine, which is required for NMDA receptor activation by glutamate. The putative antipsychotic RG1678 (also known as bitopertin) is a potent, selective, non-competitive and reversible inhibitor of GlyT1. This enhances NMDA receptor function and has been found to normalize perturbed dopaminergic as well as glutamatergic transmission in animal models [31]. RG1678 is currently under investigation in multiple clinical trials. One study has reported statistically significant and clinically meaningful improvement in negative symptoms in a placebo controlled RCT of over 300 patients [32]. Last but not least, the tetracycline antibiotic, minocycline, has been found to inhibit glutamate release and to have complex effects at ionotropic glutamate receptors [33]. A doubleblind trial of this drug in 144 patients with early course schizophrenia found evidence of modest effectiveness against negative symptoms [34]. A large multicentre trial is currently underway in the UK [102]. Drugs with actions on other receptors
In the view of some, decreased acetylcholine transmission is relevant to the pathophysiology of schizophrenia [35]. So far, however, no muscarinic receptor agonists have entered clinical trials. Development of alpha-7 nicotinic receptor agonists is, 69
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however, ongoing [36,103]. Neurotensin, an endogenous brain peptide, has been proposed to underlie putative endophenotypes of schizophrenia, such as disruption of pre-pulse inhibition. The neurotensin analogue NT69L has actions in animal models of psychosis, and has been proposed as a potential novel antipsychotic [37]. While tetrahydrocannabinol, the main active ingredient of cannabis is almost certainly psychotogenic, another constituent, cannabidiol has been claimed to have antipsychotic properties [38]. A recent trial [39] reported encouraging results in 42 acute schizophrenic in patients treated with either cannabidiol or amisulpride.
negative symptoms or TAU. They found significant improvement in one subscale of the Scale for the Assessment of Negative Symptoms (SANS), avolition-apathy, but not in three others. This study also found a significant improvement in overall functioning, but this finding has been criticized on the grounds of selective reporting [49]. The second study [50] compared 9 months of CBT to cognitive remediation (a therapy deliberately chosen to control for the non-specific effects of psychological intervention on symptoms – see later) in 198 patients. No advantage for CBT was found.
Cognitive therapy
Methodological issues
Current status
Study quality remains a persistent problem in the CBT literature, with the majority of studies being small, and some being carried out under non-blind conditions. Wykes et al. [45], in the meta-analysis cited earlier, examined the moderating effect of study quality and found no evidence that it was exerting an influence on the effect size for positive symptoms. However, they used a ‘quality scale’ which combined different aspects of trial design and reporting. This approach is no longer recommended, since such scales often rate aspects of a study that bear little relationship to known sources of bias, for example, how well the trial was organized or how well the data were presented; also use of different quality scales has been found to give different results [51]. A meta-analysis rigorously examining the potential moderating effects of blindness and other sources of bias is currently lacking. Another important methodological issue in trials of psychotherapy concerns whether the therapy is compared with TAU or a control intervention (sometimes referred to as a ‘psychological placebo’). Most authorities take the position that it is necessary, or at least desirable, for evidence-based therapies to demonstrate benefits over and above what can be attributed to the non-specific effects of psychological intervention [52,53]. A few authors, however, maintain that that applying the logic of placebo-controlled trials to psychotherapy research is based on a flawed analogy [54,55]. Whatever the theoretical merits of this latter argument, the Cochrane Collaboration [56] recently found no advantage for CBT compared with other psychosocial treatments on a range of outcomes, including relapse, rehospitalization and various measures of mental state and social functioning. This applied equally to interventions that were classified as psychotherapeutically active and inactive.
Despite decidedly mixed findings in a number of large, wellcontrolled trials (e.g., [40–44], meta-analyses of CBT for schizophrenia have provided overall support for its effectiveness. Thus, Wykes et al. [45] found a pooled effect size of -0.37 (CI: -0.23 to -0.52) for positive symptoms in 32 studies carried out up to 2006 and -0.44 (CI: -0.17 to -0.70) for negative symptoms in 23 studies. A later meta-analysis carried out by the National Collaborating Centre for Mental Health (NCCMH) [104] for the NICE 2009 schizophrenia guideline [5] found smaller and not always significant effect sizes against symptoms. However, it supported an effect in reducing rehospitalization rates and shortening duration of hospitalization. Future prospects & challenges CBT for relapse prevention
Neuroleptics not only improve the symptoms of schizophrenia, but also decrease the frequency of relapse. Whether CBT shares this latter effect was examined in a large trial by Garety et al. [43], which randomized 301 schizophrenic patients to 9 months of CBT or treatment as usual (TAU). CBT was found to produce no reduction of relapse rate; in fact, more patients in the CBT group relapsed than those in the TAU group (49 vs 34%). This led the authors to state: ‘Generic CBT for psychosis is not indicated for routine relapse prevention in people recovering from a recent relapse of psychosis and should currently be reserved for those with distressing medication-unresponsive positive symptoms.’ Two further studies have examined specially adapted forms of CBT, which, rather than being directed at symptoms, use strategies directed, for example, at early warning signs of relapse. One of these found no significant advantage for relapse or re-hospitalization in 144 patients [46]. The other, however, did find a significant effect in 81 patients [47]. CBT for negative symptoms
As originally devised, CBT focuses on re-interpreting and coping with abnormal beliefs and experiences. Two recent attempts have been made to modify the technique for the purpose of ameliorating negative symptoms. Grant et al. [48] randomly assigned 60 low-functioning, neurocognitively impaired patients with schizophrenia to either 18 months of CBT adapted for 70
Expert commentary
Twenty years after clozapine was introduced (or more accurately re-introduced), why it is better than other antipsychotics remains as unknown as ever. No other atypical drugs of comparable effectiveness have been developed and those that have come to market have only at most minor therapeutic advantages. The enormous financial risk undertaken by the pharmaceutical industry in developing new drugs has instead led, predictably, to something of a focus on ‘me too’ products. This is particularly evident in the new atypical antipsychotics Expert Rev. Neurother. 14(1), (2014)
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Current & future treatment modalities in schizophrenia
introduced in the last four years, none of which has anything new to offer in terms of receptor blocking actions, or, in all probability, in terms of therapeutic superiority. The glutamate hypothesis of schizophrenia promised much but so far it has delivered no effective treatments – despite a basic research and drug development investment that must have measured in millions if not billions of dollars. Nevertheless, drug development for schizophrenia has not entirely stalled, with novel dopaminergic and non-dopaminergic strategies both being pursued. Unfortunately, several of the most interesting and original developments stem from natural substances such as cannabidiol, stepholidine and oxytocin, which may cause difficulties in terms of protection of the intellectual property rights. CBT has led to a re-evaluation of the role of psychological factors in a disorder that was, for several decades, considered largely or wholly biologically determined. While the historical importance of this should not be underestimated, the emerging picture of CBT in schizophrenia is of only minor effectiveness against positive psychotic symptoms, the symptoms it was originally developed to address. Nor are the two trials to date, which have repurposed CBT for negative symptoms encouraging, and it is clear that CBT does not help prevent relapse. But what is perhaps of most concern is the Cochrane Collaboration’s recent conclusion that CBT does not show clear and convincing advantages over other psychosocial treatments.
Review
Five-year view
Standing back from an active and quite diversified field of drug development, a few trends are discernible. First, it seems inescapable that further development of atypical antipsychotics, as they are currently conceptualized, is limited. Also facing an uncertain future is the huge research investment in glutamatergic mechanisms in schizophrenia; glutamate modifying drugs, if they survive at all, will only have a place in the treatment of negative symptoms (although this would represent an important therapeutic advance). Perhaps one or two of the drugs with novel mechanisms of action reviewed in this article will receive licenses, but probably for adjunctive use rather than as monotherapy. The question facing CBT is what will be the service implications in years to come for an intervention that is costly and labor-intensive, and whose main effect appears increasingly to be on aspects of the clinical picture other than the core symptoms of the disorder. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Clozapine shows superior efficacy to conventional antipsychotics; the occasional claims that this is not the case lack credibility. • There is an unresolved controversy over whether or not some other atypical antipsychotics have therapeutic advantages over conventional drugs. • The performance of recent entrant aytpicals has been disappointing. • Non-dopamine mechanisms of action are of great interest, but none has yet provided an effective antipsychotic drug. • There is more activity in respect of adjunctive treatment than monotherapy. • The effectiveness of cognitive therapy in schizophrenia is emerging as limited.
And Secondary Care. Gaskell and the British Psychological Society, London (2003).
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Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy Expert Rev. Neurother. 14(1), 67–73 (2014)
Peter J McKenna*1 and Ann M Mortimer2 1
FIDMAG, Germanes Hospitala`ries, and CIBERSAM, C/. Dr. Antoni Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain 2 The Eleanor Centre, 21 Eleanor Street, GRIMSBY, North East Lincolnshire, DN32 9EA, UK *Author for correspondence: [email protected]
In 60 years of use of antipsychotic drugs in schizophrenia, the only definite advance has been the introduction of clozapine. Some but not all other atypical or second-generation drugs may have small therapeutic advantages over conventional antipsychotics, but this remains controversial. New entrant atypicals seem unlikely to be therapeutically superior to conventional drugs, and glutamatergic drugs have yet to fulfill their theoretical promise. There is considerable current interest in novel mechanisms of antipsychotic action, but no such drugs have yet reached market authorization. A psychotherapeutic intervention, cognitive behavioral therapy has also found a place in the treatment of schizophrenia. However, the size of its effect against psychotic symptoms is small, and current evidence suggests no effect against negative symptoms or in reducing relapse. KEYWORDS: antipsychotic • cognitive behavioral therapy • dopamine • glutamate • mechanism of action • schizophrenia
Schizophrenia continues to present one of the greatest therapeutic challenges in psychiatry. For decades after its identification by Kraepelin and Bleuler, it was essentially an untreatable disorder, notwithstanding the sometimes enthusiastic use of measures up to and including frontal lobotomy. The serendipitous discovery of chlorpromazine in 1952 marked the beginning of the modern era of psychopharmacological treatment, which subsequently saw the introduction of over 30 further dopamine D2 receptor blocking antipsychotic drugs. However, the limitations of this form of treatment soon became apparent, and today it is accepted that conventional drugs are not curative in most cases, and that between 5 and 25% of schizophrenic patients are resistant to treatment [1]. Two developments have changed the therapeutic landscape in schizophrenia. The first was the worldwide introduction of clozapine in the early 1990s, following the demonstration by Kane and co-workers [2] that it was superior to chlorpromazine in treatmentresistant patients. This, coupled with the recognition that it did not produce Parkinsonism www.expert-reviews.com
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and tardive dyskinesia, led to the now widely accepted view that clozapine is the first significant therapeutic advance in schizophrenia since the introduction of chlorpromazine. It has also led to a search for other similar drugs, which might show greater effectiveness and/or less extrapyramidal side-effects. As a result, there are now around 12 so-called atypical or second generation antipsychotics currently in use, and more are under development. Whether some of these show superior effectiveness to conventional or first-generation antipsychotics drugs is currently the subject of intense debate. The second development has been the rise of psychological treatments in schizophrenia, in particular cognitive behavioral therapy (cognitive therapy, CBT). The pioneering study here was by Kuipers et al. [3], who found CBT to be effective compared with treatment as usual in a sample of 60 schizophrenic patients with at least one positive psychotic symptom resistant to drug treatment. More than 30 subsequent trials of CBT, large and small, have since been carried out, and have had quite varied findings. Nevertheless, based on support from meta-analysis, CBT has been
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recommended by the highly respected UK National Institute of Clinical Excellence (NICE, [4,5]), as well as by other guideline development groups around the world [6]. In this article, we provide an update of the current status of atypical antipsychotics, briefly review some important criticisms and outline possible future developments in the field. We also review the state of the evidence concerning CBT for schizophrenia, note ways in which the therapy is being extended and highlight some of the challenges it faces. Atypical & novel antipsychotic drugs Current status
A comprehensive meta-analysis of atypical versus conventional antipsychotics was carried out by Leucht et al. [7] in 2009. They found a pooled effect size of -0.52 (CI: -0.29 to -0.75; 23 studies) for clozapine on overall symptom scores, -0.31 (-0.19 to -0.44; 13 studies) for amisulpride, -0.28 (-0.18 to -0.38; 28 studies) for olanzapine and -0.13 (-0.05 to -0.22; 34 studies) for risperidone (the negative sign favors the atypical). As the confidence intervals indicate, these effect sizes were all significant, but apart from for clozapine they all fell into the ‘small’ range. Five more atypicals, aripiprazole, quetiapine, sertindole, ziprasidone and zotepine showed no significant advantage over conventional drugs. Leucht et al. [7] concluded that the superior effectiveness of clozapine was supported, and that there were smaller advantages for some but not all atypicals. While Leucht et al.’s [7] conclusions with respect to clozapine are uncontroversial, there are at least three threats to the acceptance of the finding that some other atypicals are also superior to conventional drugs. One is a longstanding but still topical argument that the apparent therapeutic superiority of these drugs simply reflects the high doses – and consequent decreased tolerability – of the typical antipsychotics used as comparators in some of the trials [8]. Thus in a meta-analysis published in 2000, Geddes et al. [9] found that an observed advantage in favor of atypical drugs become smaller as the mean dose of haloperidol or chlorpromazine used in the trials increased. Three years later, Davis et al. [10] explored the effect of comparator dose in depth in a meta-analysis that included a larger set of studies. The results of several different analyses led them to conclude that there was no significant effect of haloperidol dose on the advantage of atypical over conventional drugs. Leucht et al. [7] also examined the effect of comparator dose in their meta-analysis; once again no moderating effect was found. The second challenge is that two further recent meta-analyses, carried out on behalf of official guideline development groups in England and Canada, have failed to find clear evidence of therapeutic superiority for any atypical antipsychotics other than clozapine [5], or for all atypicals including clozapine [11]. However, it should be noted that both these meta-analyses departed somewhat from the conventional approach of pooling data from as many different sources as possible, and instead opted for a large series of smaller metaanalyses, which compared atypicals with either chlorpromazine or haloperidol, and/or which divided studies according to 68
whether the BPRS or the PANSS was used to rate symptoms and/or whether the studies were short-, medium- or long-term, and so on. At the very least, such a ‘splitting’ as opposed to ‘lumping’ approach will reduce the power of meta-analysis to detect differences between atypical and conventional antipsychotics. The failure of one of these meta-analyses to support the therapeutic superiority of clozapine [11] also lacks credibility. Perhaps the most important cautionary note is sounded by two recent, large ‘pragmatic’ trials of atypical antipsychotics. The first of these, the CATIE study [12], randomly assigned just under 1500 schizophenic patients to treatment with olanzapine, quetiapine or risperidone, or to a conventional drug, perphenazine. (A ziprasidone arm was also later added after this drug was approved for clinical used in the USA). Patients were followed under double-blind conditions for up to 18 months, with the main outcome measure being time to discontinuation of treatment. It was found that neither time to the discontinuation of treatment for any cause nor time to the discontinuation for lack of efficacy was significantly longer for quetiapine, risperidone or ziprasidone than for perphenazine; there was a significant advantage for olanzapine on both measures, but this did not survive controlling for multiple comparisons. Symptom outcomes were not examined statistically, but the authors noted that, while olanzapine produced greater reductions in scores compared with perphenazine, this was counterbalanced by smaller changes with the other atypicals. Results were similar in the CUtLASS study, an open trial, which examined 227 patients with schizophrenia whose medication was changed because of inadequate response or adverse effects [13]. The patients were randomized to either conventional or atypical treatment (not including clozapine), with the choice of individual drug being made by the treating psychiatrist. No significant advantage was found for any atypical in terms of quality of life, symptoms or associated costs of care. The findings of these trials are open to interpretation. Lieberman [14], the leader of the CATIE trial, concluded: ‘The numerous antipsychotic drugs, however they might be classified, are more similar to than different from each other. To the extent that antipsychotics differ, it is more in their side effects than therapeutic effects.’ Leucht [15], in contrast, argued that the differences between the findings of his meta-analysis and those of the CATIE study were more apparent than real. He noted that olanzapine was found to be superior on several efficacy outcomes in CATIE (drop-out due to inefficacy, time on effective treatment), and that the poor performance of risperidone in this trial could have been due to the fact that the modal dose was 3.9 mg/day, meaning that many patients would have received only 1.5 or 3 mg mg/day (guidelines suggest 2–8 mg/day). Several new entrant atypical drugs have appeared in the past few years, including iloperidone [16], blonanserin [17], asenapine [18] and lurisidone [19]. None of them have been found to be more effective than conventional antipsychotics. At the same time, they have not been found to be Expert Rev. Neurother. 14(1), (2014)
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significantly inferior to other atypicals such as olanzapine or risperidone. However, because the therapeutic advantage of these latter drugs is small, the sample sizes to convincingly demonstrate non-inferiority will need to be large. In fact, in the studies to date there are indications of numerically lower reductions in symptom scores compared with the comparator atypical, suggesting that these new drugs will ultimately not fall into the ‘slightly better than conventionals’ subcategory, if such a subcategory exists. Future prospects & challenges Dopamine receptor antagonists
The majority of ‘pipeline’ antipsychotic drugs have dopamine and other receptor affinity profiles that are not greatly different from existing drugs. Even so, it may be possible to design new drugs with combinations of affinities that avoid those known to be associated with side-effects. For instance, the combination of the ‘structural scaffolds’ of dopamine and serotonin has produced a group of azecine derivatives, which are effective in animal models of psychosis but manifest substantially better tolerability than both haloperidol and risperidone [20]. Cariprazine is a novel D3 preferring, dopamine receptor partial agonist in Phase III clinical development for the treatment of schizophrenia and bipolar mania [21]. It remains to be seen whether it affords any efficacy advantages over existing antipsychotic drugs. Nevertheless, cariprazine’s active metabolite, didesmethyl cariprazine, has a half life of 2–3 weeks, which could lead to it having potential as a once weekly oral dose formulation, something that is lacking (and arguably very much needed) in the current therapeutic armamentarium. l-stepholidine (l-SPD), a plant derived alkaloid, is a D1/ 5-HT1A agonist and a D2 antagonist. Preliminary clinical trials suggest that it improves both positive and negative symptoms, without producing significant extrapyramidal side effects [22]. Dimerization of dopamine D2 receptors is a phenomenon observed in post-mortem schizophrenia brain tissue and in experimental animals challenged with amphetamine. It is thought that the dimerized receptor complex interferes with dopamine transporter mechanisms. This may represent a promising new target for antipsychotic action in the future. Glutamatergic drugs
As a neurochemical theory of schizophrenia, the glutamate hypothesis – based on the finding that glutamate antagonists like phencyclidine and ketamine induce a psychotic state that is arguably more similar to schizophrenia than that produced by amphetamine – remains highly influential [23]. The road to glutamate-based drug treatments, however, has proved rather more rocky. Initial trials of drugs with indirect glutamate agonist actions at NMDA and/or other ionotropic glutamate receptors provided evidence for a therapeutic effect on negative, but not positive, symptoms [24]. (Direct glutamate agonists are too rapidly metabolized to be useful, and also have the potential to cause neuronal damage through excitotoxic actions.) A subsequent large trial of glycine and cycloserine in www.expert-reviews.com
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171 schizophrenic patients with persistent negative symptoms, however, failed to find evidence of significant superiority for either drug over placebo [25]. Nor did Lieberman et al. [26] find any therapeutic effect of memantine, a non-competitive antagonist at the NMDA receptor, in a placebo-controlled trial of 138 patients. A last minute reprieve for indirect glutamate agonists is not completely ruled out. Thus, a recent meta-analysis, which included both the above large negative trials [27] found evidence of small-to-moderate effectiveness against all classes of schizophrenic symptom. Even so, none of these compounds is currently the subject of trials activity. Another possible way of remediating the putative glutamatergic deficit in schizophrenia is to target metabotropic glutamate receptors. The drug LY2140023 (also known as pomaglutamed methionil), a direct agonist at this receptor, has been the subject of two published clinical trials. In the first, it was found to be almost as effective as olanzapine [28]. In the second there was a marked placebo response, from which neither olanzapine nor LY2140023 separated [29]. Lilly, the developers of the drug, have recently announced that a third trial found no superiority against placebo, and have halted further development [101]. The peptide transmitter N-acetylaspartylglutamate (NAAG) is an agonist at the metabotropic glutamate receptor, mGluR3 and is inactivated by glutamate carboxypeptidase II (GCPII). Some NAAG peptidase inhibitors such as the drugs ZJ43 and (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA) are not only effective in glutamatergic animal models of psychosis, but also block the effects of amphetamineinduced motor activity [30]. Glycine transporter 1 (GlyT1) inhibition preserves synaptic glycine, which is required for NMDA receptor activation by glutamate. The putative antipsychotic RG1678 (also known as bitopertin) is a potent, selective, non-competitive and reversible inhibitor of GlyT1. This enhances NMDA receptor function and has been found to normalize perturbed dopaminergic as well as glutamatergic transmission in animal models [31]. RG1678 is currently under investigation in multiple clinical trials. One study has reported statistically significant and clinically meaningful improvement in negative symptoms in a placebo controlled RCT of over 300 patients [32]. Last but not least, the tetracycline antibiotic, minocycline, has been found to inhibit glutamate release and to have complex effects at ionotropic glutamate receptors [33]. A doubleblind trial of this drug in 144 patients with early course schizophrenia found evidence of modest effectiveness against negative symptoms [34]. A large multicentre trial is currently underway in the UK [102]. Drugs with actions on other receptors
In the view of some, decreased acetylcholine transmission is relevant to the pathophysiology of schizophrenia [35]. So far, however, no muscarinic receptor agonists have entered clinical trials. Development of alpha-7 nicotinic receptor agonists is, 69
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however, ongoing [36,103]. Neurotensin, an endogenous brain peptide, has been proposed to underlie putative endophenotypes of schizophrenia, such as disruption of pre-pulse inhibition. The neurotensin analogue NT69L has actions in animal models of psychosis, and has been proposed as a potential novel antipsychotic [37]. While tetrahydrocannabinol, the main active ingredient of cannabis is almost certainly psychotogenic, another constituent, cannabidiol has been claimed to have antipsychotic properties [38]. A recent trial [39] reported encouraging results in 42 acute schizophrenic in patients treated with either cannabidiol or amisulpride.
negative symptoms or TAU. They found significant improvement in one subscale of the Scale for the Assessment of Negative Symptoms (SANS), avolition-apathy, but not in three others. This study also found a significant improvement in overall functioning, but this finding has been criticized on the grounds of selective reporting [49]. The second study [50] compared 9 months of CBT to cognitive remediation (a therapy deliberately chosen to control for the non-specific effects of psychological intervention on symptoms – see later) in 198 patients. No advantage for CBT was found.
Cognitive therapy
Methodological issues
Current status
Study quality remains a persistent problem in the CBT literature, with the majority of studies being small, and some being carried out under non-blind conditions. Wykes et al. [45], in the meta-analysis cited earlier, examined the moderating effect of study quality and found no evidence that it was exerting an influence on the effect size for positive symptoms. However, they used a ‘quality scale’ which combined different aspects of trial design and reporting. This approach is no longer recommended, since such scales often rate aspects of a study that bear little relationship to known sources of bias, for example, how well the trial was organized or how well the data were presented; also use of different quality scales has been found to give different results [51]. A meta-analysis rigorously examining the potential moderating effects of blindness and other sources of bias is currently lacking. Another important methodological issue in trials of psychotherapy concerns whether the therapy is compared with TAU or a control intervention (sometimes referred to as a ‘psychological placebo’). Most authorities take the position that it is necessary, or at least desirable, for evidence-based therapies to demonstrate benefits over and above what can be attributed to the non-specific effects of psychological intervention [52,53]. A few authors, however, maintain that that applying the logic of placebo-controlled trials to psychotherapy research is based on a flawed analogy [54,55]. Whatever the theoretical merits of this latter argument, the Cochrane Collaboration [56] recently found no advantage for CBT compared with other psychosocial treatments on a range of outcomes, including relapse, rehospitalization and various measures of mental state and social functioning. This applied equally to interventions that were classified as psychotherapeutically active and inactive.
Despite decidedly mixed findings in a number of large, wellcontrolled trials (e.g., [40–44], meta-analyses of CBT for schizophrenia have provided overall support for its effectiveness. Thus, Wykes et al. [45] found a pooled effect size of -0.37 (CI: -0.23 to -0.52) for positive symptoms in 32 studies carried out up to 2006 and -0.44 (CI: -0.17 to -0.70) for negative symptoms in 23 studies. A later meta-analysis carried out by the National Collaborating Centre for Mental Health (NCCMH) [104] for the NICE 2009 schizophrenia guideline [5] found smaller and not always significant effect sizes against symptoms. However, it supported an effect in reducing rehospitalization rates and shortening duration of hospitalization. Future prospects & challenges CBT for relapse prevention
Neuroleptics not only improve the symptoms of schizophrenia, but also decrease the frequency of relapse. Whether CBT shares this latter effect was examined in a large trial by Garety et al. [43], which randomized 301 schizophrenic patients to 9 months of CBT or treatment as usual (TAU). CBT was found to produce no reduction of relapse rate; in fact, more patients in the CBT group relapsed than those in the TAU group (49 vs 34%). This led the authors to state: ‘Generic CBT for psychosis is not indicated for routine relapse prevention in people recovering from a recent relapse of psychosis and should currently be reserved for those with distressing medication-unresponsive positive symptoms.’ Two further studies have examined specially adapted forms of CBT, which, rather than being directed at symptoms, use strategies directed, for example, at early warning signs of relapse. One of these found no significant advantage for relapse or re-hospitalization in 144 patients [46]. The other, however, did find a significant effect in 81 patients [47]. CBT for negative symptoms
As originally devised, CBT focuses on re-interpreting and coping with abnormal beliefs and experiences. Two recent attempts have been made to modify the technique for the purpose of ameliorating negative symptoms. Grant et al. [48] randomly assigned 60 low-functioning, neurocognitively impaired patients with schizophrenia to either 18 months of CBT adapted for 70
Expert commentary
Twenty years after clozapine was introduced (or more accurately re-introduced), why it is better than other antipsychotics remains as unknown as ever. No other atypical drugs of comparable effectiveness have been developed and those that have come to market have only at most minor therapeutic advantages. The enormous financial risk undertaken by the pharmaceutical industry in developing new drugs has instead led, predictably, to something of a focus on ‘me too’ products. This is particularly evident in the new atypical antipsychotics Expert Rev. Neurother. 14(1), (2014)
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Current & future treatment modalities in schizophrenia
introduced in the last four years, none of which has anything new to offer in terms of receptor blocking actions, or, in all probability, in terms of therapeutic superiority. The glutamate hypothesis of schizophrenia promised much but so far it has delivered no effective treatments – despite a basic research and drug development investment that must have measured in millions if not billions of dollars. Nevertheless, drug development for schizophrenia has not entirely stalled, with novel dopaminergic and non-dopaminergic strategies both being pursued. Unfortunately, several of the most interesting and original developments stem from natural substances such as cannabidiol, stepholidine and oxytocin, which may cause difficulties in terms of protection of the intellectual property rights. CBT has led to a re-evaluation of the role of psychological factors in a disorder that was, for several decades, considered largely or wholly biologically determined. While the historical importance of this should not be underestimated, the emerging picture of CBT in schizophrenia is of only minor effectiveness against positive psychotic symptoms, the symptoms it was originally developed to address. Nor are the two trials to date, which have repurposed CBT for negative symptoms encouraging, and it is clear that CBT does not help prevent relapse. But what is perhaps of most concern is the Cochrane Collaboration’s recent conclusion that CBT does not show clear and convincing advantages over other psychosocial treatments.
Review
Five-year view
Standing back from an active and quite diversified field of drug development, a few trends are discernible. First, it seems inescapable that further development of atypical antipsychotics, as they are currently conceptualized, is limited. Also facing an uncertain future is the huge research investment in glutamatergic mechanisms in schizophrenia; glutamate modifying drugs, if they survive at all, will only have a place in the treatment of negative symptoms (although this would represent an important therapeutic advance). Perhaps one or two of the drugs with novel mechanisms of action reviewed in this article will receive licenses, but probably for adjunctive use rather than as monotherapy. The question facing CBT is what will be the service implications in years to come for an intervention that is costly and labor-intensive, and whose main effect appears increasingly to be on aspects of the clinical picture other than the core symptoms of the disorder. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Clozapine shows superior efficacy to conventional antipsychotics; the occasional claims that this is not the case lack credibility. • There is an unresolved controversy over whether or not some other atypical antipsychotics have therapeutic advantages over conventional drugs. • The performance of recent entrant aytpicals has been disappointing. • Non-dopamine mechanisms of action are of great interest, but none has yet provided an effective antipsychotic drug. • There is more activity in respect of adjunctive treatment than monotherapy. • The effectiveness of cognitive therapy in schizophrenia is emerging as limited.
And Secondary Care. Gaskell and the British Psychological Society, London (2003).
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