Eur Arch Psychiatry Clin Neurosci DOI 10.1007/s00406-015-0596-y
INVITED REVIEW
Pharmacological treatment of negative symptoms in schizophrenia Hans‑Jürgen Möller1 · Pal Czobor2,3
Received: 20 March 2015 / Accepted: 23 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Effective treatment of negative symptoms is one of the most important unmet needs in schizophrenic disorders. Because the evidence on current psychopharmacological treatments is unclear, the authors reviewed the findings published to date by searching PubMed with the keywords negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy and identifying additional articles in the reference lists of the resulting publications. The findings presented here predominantly focus on results of meta-analyses. Evidence for efficacy of current psychopharmacological medications is difficult to assess because of methodological problems and inconsistent results. In general, the secondgeneration antipsychotics (SGAs) do not appear to have good efficacy in negative symptoms, although some show better efficacy than first-generation antipsychotics, some of which also demonstrated efficacy in negative symptoms. Specific trials on predominant persistent negative symptoms are rare and have been performed with only a few SGAs. More often, trials on somewhat persistent negative symptoms evaluate add-on strategies to ongoing antipsychotic treatment. Such trials, mostly on modern antidepressants, have demonstrated some efficacy. Several trials with small samples have evaluated add-on treatment with glutamatergic compounds, such as the naturally occurring amino
* Hans‑Jürgen Möller hans‑[email protected]‑muenchen.de 1
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany
2
Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
3
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
acids glycine and d-serine and new pharmacological compounds. The results are highly inconsistent, although overall efficacy results appear to be positive. The unsatisfactory and inconsistent results can be partially explained by methodological problems. These problems need to be solved in the future, and the authors propose some possible solutions. Further research is required to identify effective treatment for the negative symptoms of schizophrenia. Keywords Negative symptoms · Pharmacological treatment · Antipsychotics · Antidepressants · Glutamatergic compounds
Introduction During the last quarter century, efforts to identify effective schizophrenia medications have been directed towards developing broad-spectrum, disease-specific agents [73]. These agents, the second-generation antipsychotics (SGAs), are intended to target all relevant symptom domains, including positive, negative and depressive symptoms and cognitive impairments. SGAs have been extensively studied in randomised clinical trials (RCTs), which included comparisons with first-generation antipsychotics (FGAs). Although some of the SGAs have clear advantages in terms of a lower liability for extrapyramidal symptoms (EPS), in general their efficacy in treating negative symptoms is not as high as originally expected [56, 72] and only some of them are superior to FGAs [48]. The current view, as presented in evidence-based international guidelines, is that antipsychotics in general, even SGAs, have only modest benefits in treating negative symptoms [22]. Consequently, add-on treatments, predominantly antidepressants and glutamatergic compounds, have been evaluated
13
as a necessary approach to overcome the unmet needs in this field of schizophrenia treatment [19, 57]. However, the findings regarding these comedications are far from satisfactory. Given the high prevalence and the not only acute but often persistent character of the negative symptoms of schizophrenia [6, 55, 58, 68], negative symptoms continue to represent a serious unmet therapeutic need [55] and consequently a key target for current and future drug development. Moreover, since they play a central role in functional impairment, in recent decades they have received growing attention from health policy-makers. In the USA, this increasing interest from health policymakers was illustrated by the National Institute of Mental Health (NIMH) Consensus Development Conference on Negative Symptoms in 2005 [39], which aimed to address some of the key issues that need to be resolved in order to implement clinical trials for therapeutic interventions for negative symptoms. There were several follow-ups to this initial meeting, including two Workshops on Methodological Issues in Negative Symptoms at the International Society for CNS Clinical Trials and Methodology (ISCTM) conferences in 2009 and 2010 [54], with participants from academia, the NIMH, the pharmaceutical industry and regulatory agencies, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the increasing attention paid by healthcare policy-makers to negative symptoms, especially predominant or persistent negative symptoms, and the obvious unmet needs, so far no drug has been received specific FDA approval for the treatment of negative symptoms. In Europe, the EMA has thus far licensed only one antipsychotic, amisulpride, that in the summary product characteristics (SPC) specifically mentions ‘patients with predominant negative symptoms’ besides the general indication schizophrenic disorders with positive and negative symptoms. In the light of this and the fact that the SGAs have not met the early hopes of being highly effective in negative symptoms, research efforts by both academia and industry are expected to intensify in order to develop more efficacious therapeutic approaches for negative symptoms. To evaluate the situation regarding treatment of negative symptoms, the authors searched PubMed with the following keywords: negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy. Only RCTs published in English or German between 1990 and 2014 were considered. Additional articles were then identified from the reference lists of the resulting publications. The findings presented here focus on the results of meta-analyses. The authors first describe the results of RCTs on the drug treatment of negative symptoms, starting with the
13
Eur Arch Psychiatry Clin Neurosci
monotherapy studies on antipsychotics and followed by the add-on studies with antidepressants and glutamatergic compounds. For reasons of space, other compounds that received some interest but were not intensively or appropriately studied in the indication negative symptoms, for example alpha-7 nicotinic agents, modafinil and lisdexamfetamine, will not be covered [2]. Second, the authors briefly describe recent developments in the methodological demands for drug trials on negative symptoms.
Efficacy of antipsychotics in negative symptoms In most large phase III trials or other RCTs of antipsychotics, negative symptoms are not the primary outcome measure but rather a secondary outcome parameter. As a consequence, the results of these studies can only be interpreted as demonstrating effects on negative symptoms secondary to positive symptoms in patients with an acute schizophrenic episode. The results of these studies have been summarised in several reviews, including three meta-analyses by Leucht et al. [46, 48, 49]. The results of these three meta-analyses will be briefly summarised below. The first meta-analysis compared SGAs with FGAs [48] and included 150 double blind, mostly short-term studies, with a total of N = 21,533 participants. RCTs that compared oral SGAs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) with FGAs in patients with schizophrenia or related disorders (schizoaffective, schizophreniform or delusional disorders), irrespective of diagnostic criteria, were eligible for inclusion in the review. The optimum doses of SGAs were selected in fixed-dose studies. Studies were included that allowed switching of medications between groups. Comparator drugs included haloperidol, chlorpromazine, perphenazine, fluphenazine, flupenthixol, perazine, thioridazine, levomepromazine, clopenthixol, zuclopenthixol, mosapramine, thiothixene, clomipramine, trifluoperazine, periciacine and any FGA. Outcomes of interest included overall efficacy; positive, negative and depressive symptoms; and relapse, quality of life, EPS, weight gain and sedation. Outcome measurements included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression scale (CGI). The majority of included studies had a duration of 12 weeks or less. Pooled results showed that overall efficacy was statistically greater for four SGAs with small to medium effect sizes: amisulpride −0.31 (95 % CI −0.44 to −0.19, p
INVITED REVIEW
Pharmacological treatment of negative symptoms in schizophrenia Hans‑Jürgen Möller1 · Pal Czobor2,3
Received: 20 March 2015 / Accepted: 23 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Effective treatment of negative symptoms is one of the most important unmet needs in schizophrenic disorders. Because the evidence on current psychopharmacological treatments is unclear, the authors reviewed the findings published to date by searching PubMed with the keywords negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy and identifying additional articles in the reference lists of the resulting publications. The findings presented here predominantly focus on results of meta-analyses. Evidence for efficacy of current psychopharmacological medications is difficult to assess because of methodological problems and inconsistent results. In general, the secondgeneration antipsychotics (SGAs) do not appear to have good efficacy in negative symptoms, although some show better efficacy than first-generation antipsychotics, some of which also demonstrated efficacy in negative symptoms. Specific trials on predominant persistent negative symptoms are rare and have been performed with only a few SGAs. More often, trials on somewhat persistent negative symptoms evaluate add-on strategies to ongoing antipsychotic treatment. Such trials, mostly on modern antidepressants, have demonstrated some efficacy. Several trials with small samples have evaluated add-on treatment with glutamatergic compounds, such as the naturally occurring amino
* Hans‑Jürgen Möller hans‑[email protected]‑muenchen.de 1
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany
2
Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
3
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
acids glycine and d-serine and new pharmacological compounds. The results are highly inconsistent, although overall efficacy results appear to be positive. The unsatisfactory and inconsistent results can be partially explained by methodological problems. These problems need to be solved in the future, and the authors propose some possible solutions. Further research is required to identify effective treatment for the negative symptoms of schizophrenia. Keywords Negative symptoms · Pharmacological treatment · Antipsychotics · Antidepressants · Glutamatergic compounds
Introduction During the last quarter century, efforts to identify effective schizophrenia medications have been directed towards developing broad-spectrum, disease-specific agents [73]. These agents, the second-generation antipsychotics (SGAs), are intended to target all relevant symptom domains, including positive, negative and depressive symptoms and cognitive impairments. SGAs have been extensively studied in randomised clinical trials (RCTs), which included comparisons with first-generation antipsychotics (FGAs). Although some of the SGAs have clear advantages in terms of a lower liability for extrapyramidal symptoms (EPS), in general their efficacy in treating negative symptoms is not as high as originally expected [56, 72] and only some of them are superior to FGAs [48]. The current view, as presented in evidence-based international guidelines, is that antipsychotics in general, even SGAs, have only modest benefits in treating negative symptoms [22]. Consequently, add-on treatments, predominantly antidepressants and glutamatergic compounds, have been evaluated
13
as a necessary approach to overcome the unmet needs in this field of schizophrenia treatment [19, 57]. However, the findings regarding these comedications are far from satisfactory. Given the high prevalence and the not only acute but often persistent character of the negative symptoms of schizophrenia [6, 55, 58, 68], negative symptoms continue to represent a serious unmet therapeutic need [55] and consequently a key target for current and future drug development. Moreover, since they play a central role in functional impairment, in recent decades they have received growing attention from health policy-makers. In the USA, this increasing interest from health policymakers was illustrated by the National Institute of Mental Health (NIMH) Consensus Development Conference on Negative Symptoms in 2005 [39], which aimed to address some of the key issues that need to be resolved in order to implement clinical trials for therapeutic interventions for negative symptoms. There were several follow-ups to this initial meeting, including two Workshops on Methodological Issues in Negative Symptoms at the International Society for CNS Clinical Trials and Methodology (ISCTM) conferences in 2009 and 2010 [54], with participants from academia, the NIMH, the pharmaceutical industry and regulatory agencies, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the increasing attention paid by healthcare policy-makers to negative symptoms, especially predominant or persistent negative symptoms, and the obvious unmet needs, so far no drug has been received specific FDA approval for the treatment of negative symptoms. In Europe, the EMA has thus far licensed only one antipsychotic, amisulpride, that in the summary product characteristics (SPC) specifically mentions ‘patients with predominant negative symptoms’ besides the general indication schizophrenic disorders with positive and negative symptoms. In the light of this and the fact that the SGAs have not met the early hopes of being highly effective in negative symptoms, research efforts by both academia and industry are expected to intensify in order to develop more efficacious therapeutic approaches for negative symptoms. To evaluate the situation regarding treatment of negative symptoms, the authors searched PubMed with the following keywords: negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy. Only RCTs published in English or German between 1990 and 2014 were considered. Additional articles were then identified from the reference lists of the resulting publications. The findings presented here focus on the results of meta-analyses. The authors first describe the results of RCTs on the drug treatment of negative symptoms, starting with the
13
Eur Arch Psychiatry Clin Neurosci
monotherapy studies on antipsychotics and followed by the add-on studies with antidepressants and glutamatergic compounds. For reasons of space, other compounds that received some interest but were not intensively or appropriately studied in the indication negative symptoms, for example alpha-7 nicotinic agents, modafinil and lisdexamfetamine, will not be covered [2]. Second, the authors briefly describe recent developments in the methodological demands for drug trials on negative symptoms.
Efficacy of antipsychotics in negative symptoms In most large phase III trials or other RCTs of antipsychotics, negative symptoms are not the primary outcome measure but rather a secondary outcome parameter. As a consequence, the results of these studies can only be interpreted as demonstrating effects on negative symptoms secondary to positive symptoms in patients with an acute schizophrenic episode. The results of these studies have been summarised in several reviews, including three meta-analyses by Leucht et al. [46, 48, 49]. The results of these three meta-analyses will be briefly summarised below. The first meta-analysis compared SGAs with FGAs [48] and included 150 double blind, mostly short-term studies, with a total of N = 21,533 participants. RCTs that compared oral SGAs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) with FGAs in patients with schizophrenia or related disorders (schizoaffective, schizophreniform or delusional disorders), irrespective of diagnostic criteria, were eligible for inclusion in the review. The optimum doses of SGAs were selected in fixed-dose studies. Studies were included that allowed switching of medications between groups. Comparator drugs included haloperidol, chlorpromazine, perphenazine, fluphenazine, flupenthixol, perazine, thioridazine, levomepromazine, clopenthixol, zuclopenthixol, mosapramine, thiothixene, clomipramine, trifluoperazine, periciacine and any FGA. Outcomes of interest included overall efficacy; positive, negative and depressive symptoms; and relapse, quality of life, EPS, weight gain and sedation. Outcome measurements included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression scale (CGI). The majority of included studies had a duration of 12 weeks or less. Pooled results showed that overall efficacy was statistically greater for four SGAs with small to medium effect sizes: amisulpride −0.31 (95 % CI −0.44 to −0.19, p
