Meta-analysis of noradrenergic and specific serotonergic antidepressant use in schizophrenia

Transcription

1 International Journal of Neuropsychopharmacology (2014), 17, CINP 2013 doi: /s Meta-analysis of noradrenergic and specific serotonergic antidepressant use in schizophrenia REVIEW Taro Kishi and Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan Abstract We examined whether noradrenergic and specific serotonergic antidepressants (NaSSAs: mirtazapine and mianserin), as augmentation therapy, have therapeutic potential for schizophrenia treatment. A systematic review was conducted of PubMed, Cochrane Library and PsycINFO in December 2012 and meta-analyses of double-blind, randomized placebo-controlled trials were performed. Standardized mean difference (SMD), risk ratio (RR), number-needed-to-treat (NNT), number-needed-to-harm (NNH) and 95% confidence intervals (CI) were calculated. Results were across 12 studies and 362 patients were included (mirtazapine: seven trials and 221 patients; mianserin: five trials and 141 patients). NaSSA augmentation therapy was superior to placebo in overall symptoms (S.M.D.= 0.75, CI 1.24 to 0.26, p=0.003, N=11, n=301), negative symptoms (S.M.D.= 0.88, CI 1.41 to 0.34, p=0.001, N=9, n=240) and response rate (RR=0.71, CI , p=0.002, NNT=4, p< , N=6, n=163). There was no significant difference in positive symptoms, depressive symptoms or discontinuation rate between NaSSAs and placebo treatments. In addition, no patients who received NaSSAs developed worsening psychosis during the study. For individual NaSSAs, mirtazapine was superior to placebo in overall symptoms (S.M.D. =0.98, CI= 1.74 to 0.22, p=0.01, N=7, n=194), negative symptoms (S.M.D.= 1.25, CI 1.88 to 0.62, p=0.0001, N=6, n=172) and response rate (RR=0.70, p=0.04, NNT=4, p=0.0004, N=4, n=119). Moreover, NaSSAs were associated with reduced akathisia score (p< ) and extrapyramidal symptom scales (p=0.01). However, NaSSAs caused drowsiness/sedation/somnolence compared with placebo (RR=3.52, p=0.002, NNT=6, p=0.01, N=8, n=209). Our results indicate that NaSSA (especially mirtazapine) augmentation therapy improved overall and negative symptoms in patients with schizophrenia. Because the included studies were small, the results should be treated with caution. Received 20 February 2013; Reviewed 20 March 2013; Revised 12 April 2013; Accepted 14 May 2013; First published online 3 July 2013 Key words: Meta-analysis, mianserin, mirtazapine, NaSSAs, schizophrenia. Introduction The negative symptoms of schizophrenia, including problems with motivation, social withdrawal, diminished affective responsiveness, speech and movement, contribute more to poor functional outcomes and quality of life for individuals with schizophrenia than do positive symptoms (Milev et al., 2005; Foussias and Remington, 2010). Moreover, the severity of negative symptoms is associated with cognitive dysfunctions Address for correspondence: Dr T. Kishi, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi , Japan. Tel.: Fax: tarok@fujita-hu.ac.jp (Kishi et al., 2010). However, available antipsychotic therapy is not relatively effective for treating negative symptoms and cognitive dysfunction of schizophrenia (Goldberg et al., 2007, 2010; Leucht et al., 2009a, b). Recently, Singh et al. (2010) reported the metaanalysis of antidepressant augmentation therapy of efficacy in negative symptoms of schizophrenia. Fluoxetine and trazodone improved negative symptoms compared with placebo. However, mirtazapine and mianserin were not more efficacious on negative symptoms than placebo. Mirtazapine and mianserin are also called noradrenergic and specific serotonergic antidepressants (NaSSAs) and are differentiated from other antidepressants (Croom et al., 2009). Mirtazapine has a tetracyclic structure similar to that of mianserin. NaSSAs are an antagonist for noradrenaline (NA) α 2 autoreceptors, which results in enhanced

2 344 T. Kishi and N. Iwata release of NA from noradrenergic terminals, and for NA α 2 heteroreceptors (receptors on serotonin (5-HT) neurons), which increase serotonin release from serotonergic terminals. The increased release of NA also increases the firing of serotonergic neurons through stimulation of α 1 receptors. Both NA and 5-HT functions are increased. In addition, mirtazapine blocks post-synaptic 5-HT 2 and 5-HT 3 (but not 5-HT 1A ) receptors; it is these actions that give rise to the description specific serotonergic. The net result is to increase NA and 5-HT transmission. Blockade of 5-HT 2 and 5-HT 3 receptors means that side-effects (insomnia, agitation, sexual dysfunction and nausea) resulting from stimulation of these receptors should be minimized. In addition, mirtazapine and mianserin also block histamine H 1 receptors very strongly, thus causing sedation, but have little effect on acetylcholine, dopamine, or NA α 1 receptors (Croom et al., 2009; Watanabe et al., 2011). Although Singh et al. (2010) reported that mirtazapine and mianserin were not superior to placebo in negative symptoms (four studies: Berk et al., 2001, 2009; Zoccali et al., 2004; Joffe et al., 2009), recently, two randomized placebo-controlled trials (RCTs) of mirtazapine were reported (Abbasi et al., 2010; Cho et al., 2011). In addition, some studies reported that mirtazapine provided greater benefit for the improvement of overall symptoms, as well as negative symptoms, compared with placebo (Zoccali et al., 2004; Joffe et al., 2009; Abbasi et al., 2010). However, the results of other studies were inconsistent (Berk et al., 2001, 2009; Cho et al., 2011). Reasons for these discrepant results may be related to the small sample sizes of these trials, which had 9 20 participants in each treatment arm, and disparate outcome measures. A meta-analysis can increase the statistical power for group comparisons and can overcome the limitation of sample size in conditions where larger trials are lacking (Cohn and Becker, 2003). Moreover, using random effects models and standardized mean difference (S.M.D.) analyses, outcomes with different metrics can be combined (DerSimonian and Laird, 1986). Moreover, the study needed to describe the clinical pharmacological profile (efficacy: overall, positive, negative and depressive symptoms; tolerability: discontinuation; safety: each side-effect) of NaSSA augmentation therapy in patients with schizophrenia by conducting a systematic review and a meta-analysis. Therefore, we carried out a systematic review and meta-analysis of RCTs of NaSSA augmentation therapy in schizophrenia. Given the involvement of 5-HT and NA mechanisms in the beneficial effects on psychopathology, we hypothesized that NaSSA augmentation therapy might be superior to placebo in one or more efficacy outcomes. Method Search strategy, data extraction, and outcomes To identify relevant studies, we searched PubMed, the Cochrane Library databases and PsycINFO citations in December 2012, using the following keywords: aptazapine (Liebman et al., 1983), esmirtazapine (Pinder and van Delft, 1983), mirtazapine, mianserin or setiptiline (Niho et al., 1986; Yamada and Furukawa, 1991) and schizophrenia. Inclusion criteria were double-blind, placebo-controlled, RCTs of NaSSA augmentation therapy. Complementing the electronic search, pertinent review articles, prior meta-analyses and reference lists from identified studies were handsearched for additional studies eligible for inclusion in this meta-analysis. Two authors (T. K. and N. I.) double-checked the inclusion and exclusion criteria of the identified studies. When data required for the meta-analysis were missing, the first/corresponding authors were contacted for additional information. Additional, unpublished data were provided for this meta-analysis by Dr Seetal Dodd. Two authors (T. K. and N. I.) independently extracted data and checked and entered data into the Review Manager. Data synthesis We included the outcomes of this meta-analysis, which could include at least three studies in each outcome (Supplementary Table S1). The primary outcomes were the overall [total Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962] end-point scores from two studies, change of total BPRS scores from baseline to end-point from three studies, total Positive and Negative Syndrome Scale (PANSS; Kay et al., 1989) end-point score from three studies and change of total PANSS scores from baseline to end-point from three studies), positive [change of positive BPRS scores from baseline to end-point from one study, positive PANSS end-point score from four studies, change of positive PANSS scores from baseline to end-point from two studies, Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1985) end-point score from two studies and change of SAPS scores from baseline to end-point from one study] and negative symptoms [negative PANSS end-point score from two studies, change of negative PANSS scores from baseline to end-point from two studies, Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1982) end-point score from three studies

3 NaSSAs for schizophrenia 345 and change of SANS scores from baseline to end-point from two studies]. The secondary outcomes were PANSS general subscale score (change of PANSS general scores from baseline to end-point from two studies, PANSS general score from three studies), depressive symptoms [the Hamilton Rating Scale for Depression (HAMD; Hamilton, 1960) end-point score from three studies, change of negative HAMD scores from baseline to end-point from three studies, change of the Calgary Depression Rating Scale (CDSS; Addington et al., 1990) from baseline to end-point from one study and BPRS depression end-point score from one study], Clinical Global Impressions-Severity of Illness (CGI-S; Guy and Bonato, 1970) end-point score from two studies and change of score from baseline to end-point from one study, response rate (the definition of responder based on original study, 520% reduction in SANS total score from two studies, 530% reduction in SANS total score from one study, 520% reduction in PANSS total score from one study, 550% reduction in PANSS total score from one study and 525% reduction in BPRS total score from one study) and discontinuation due to all-cause and side-effect. Moreover, we analysed reported adverse effects, such as drowsiness/sedation/ somnolence, as long as 53 studies contributed data to the analyses. For akathisia and extrapyramidal symptoms (EPS), we used Barnes Akathisia Rating Scale (BAS; Barnes, 1989) and Simpson Angus Scale (SAS; Simpson and Angus, 1970), respectively. Statistical analysis Meta-analysis was conducted according to the guidelines from the Preferred Reporting Items for Systematic reviews and Meta-Analysis group (Moher et al., 2009). We based the analyses on intent-to-treat (ITT) or modified ITT data (i.e. at least one dose or at least one follow-up assessment). However, the data of completer analysis were not excluded to obtain as much information as possible (Poyurovsky et al., 1999; Berk et al., 2009). In addition, the Abbasi et al. (2010) study did not report actual numbers of patients who were analysed for all outcomes. However, they mentioned ITT analysis with last observation carried forward procedure was performed and the sample size was calculated at least 15 in each group. Therefore, we substituted n=15 as the number of patients who were analysed. The meta-analysis was performed using Review Manager, Version 5.1 for Windows (Review Manager version 5.0, Cochrane Collaboration, To combine studies, the random effects model by Der-Simonian and Laird (1986) was used in all cases. This method is more conservative, because it statistically accounts for the possibility that the meta-analysed studies and samples are heterogeneous. For continuous data, S.M.D. was used, combining effect size (Hedges g) data. For dichotomous data, pooled estimates of risk ratio (RR) were calculated together with 95% confidence intervals (CI). In the case of significant group differences in categorical variables, the number-needed-to-treat (NNT) or the number-needed-to-harm (NNH) for adverse effects was calculated. NNH was derived from the risk difference (RD) using the following formula: NNH = 1/RD, with the 95% CI of NNH being the inverse of the upper and lower limits of the 95% CI of the RD. We explored study heterogeneity using the χ 2 test of homogeneity (p <0.05) together with I 2 statistics, considering values of 550% to reflect considerable heterogeneity (Higgins et al., 2003). In cases of I 2 values >50% for the primary outcomes, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. Finally, funnel plots were inspected visually to explore the possibility of publication bias. Results Search results and study, patient and treatment characteristics The online search yielded 108 references using the above mentioned key words (mirtazapine and schizophrenia = 42 references, mianserin and schizophrenia = 65 references and setiptiline and schizophrenia = 1 reference). We excluded 90 studies based on the title and abstract review. Six studies were excluded based on full-text review because of same study. The online search identified 12 studies (Hayashi et al., 1997; Poyurovsky et al., 1999, 2003a, b; Berk et al., 2001, 2009; Shiloh et al., 2002; Zoccali et al., 2004; Miodownik et al., 2006; Joffe et al., 2009; Abbasi et al., 2010; Cho et al., 2011; Fig. 1). Although we conducted a hand-search using review articles, we did not identify any additional studies included in the metaanalysis. Twelve studies and 362 patients were included (mirtazapine: seven trials and 221 patients; mianserin: five trials and 141 patients; Table 1). The mean age of the study population was 38.1 yr. All studies were double-blind RCTs and published in English. Five of the 12 studies were conducted in Israel (Poyurovsky et al., 1999, 2003a, b; Shiloh et al., 2002; Miodownik et al., 2006) and no study was conducted in the USA. The mean study duration was 33.3 d (range 5 56 d). Sample sizes ranged from 18 40, with 9 20 participants being randomized to

4 346 T. Kishi and N. Iwata KEYWORDS aptazapine and schizophrenia 0 reference esmirtazapine and schizophrenia 0 reference mianserin and schizophrenia 65 references mirtazapine and schizophrenia 42 references setiptiline and schizophrenia 1 reference Number of studies excluded through screening: 90 references Number of full-text articles assessed for eligibility: 18 references Number of articles excluded Same study: 6 references Number of studies included in the meta-analysis: 12 references Fig. 1. Preferred reporting items for systematic reviews and meta-analysis flow diagram. each of the groups. The study population was nine trials focused on only schizophrenia patients and three trials focused on schizophrenia/schizoaffective disorder/schizophreniform disorder. Antipsychotics studied in the RCTs included risperidone (two trials), haloperidol (one trial), clozapine (one trial), mixed second generation antipsychotic (SGA; one trial), mixed first generation antipsychotic (FGA; six trials) and mixed antipsychotic (one trial). All included studies were double-blind, randomized, placebocontrolled trials and stated the detailed information about study design. However, two studies used completer analysis (Supplementary Table S1). Results of efficacy NaSSA augmentation therapy was superior to placebo in overall symptoms (S.M.D.= 0.75, CI 1.24, 0.26, p = 0.003, I 2 =74, N=11, n=301; Supplementary Fig. S1), negative symptoms (S.M.D.= 0.88, CI 1.41 to 0.34, p=0.001, I 2 =72, N=9, n=240; Supplementary Fig. S2) and response rate (RR = 0.71, CI , p = 0.002, NNT=4, p< , N=6, n=163; Table 2). NaSSA augmentation therapy was also better than placebo for providing marginal improvement of depressive symptoms (S.M.D.= 0.24, p=0.09, N=8, n=207). However, NaSSA augmentation therapy was not superior to placebo in positive symptoms (S.M.D.= 0.28, p = 0.18, N =9, n = 240), CGI-S (S.M.D.= 0.65, p = 0.13, N=3, n =100) or PANSS general score (S.M.D.= 0.31, p=0.22, N=5, n=152; Table 2). The data in each efficacy outcome were simulated with no publication bias. For individual NaSSAs, mirtazapine was superior to placebo in overall symptoms (S.M.D.= 0.98, CI 1.74 to 0.22, p = 0.01, N =7, n = 194), negative symptoms (S.M.D.= 1.25, CI 1.88 to 0.62, p = , N =6, n=172) and response rate (RR =0.70, p=0.04, NNT =4, p = , N = 4, n = 119; Table 2). Mirtazapine was also better than placebo for providing marginal improvement of depressive symptoms (S.M.D.= 0.35, p=0.09, N =5, n=139) and CGI-S scores (S.M.D.= 0.63, p = 0.05, N =1, n = 39). Mianserin was superior to placebo in only response rate (RR = 0.66, p = 0.01, NNT =3, p=0.0007, N=2, n=44; Table 2). We found significant heterogeneity in overall, positive and negative symptoms between NaSSAs and the placebo treatment group. However, there was no significant heterogeneity in these outcomes in mianserin and placebo. Therefore, we performed the sensitivity analysis of only meta-analysis of mirtazapine to seek out confounding factors. When excluding the data of completer analysis (Berk et al., 2009) and clozapine trial (Zoccali et al., 2004) in overall symptoms, the significant heterogeneity disappeared (S.M.D.= 0.84, CI 1.19 to 0.49, p< , I 2 =0, N=5, n =139). Also, when excluding the Joffe et al. (2009) study in positive symptoms, the significant heterogeneity disappeared (S.M.D.= 0.02, CI 0.51 to 0.46, p = 0.92, I 2 =48, N =5, n=133). In addition, when excluding the data of completer analysis (Berk et al., 2009), significant heterogeneity was not found (S.M.D.= 1.48, CI 1.86 to 1.09, p< , I 2 =0%, N=5, n=139). However, the results of these outcomes did not change. While mirtazapine augmentation therapy in patients primarily treated with SGAs was significantly superior to placebo for negative symptoms (S.M.D.= 1.17, CI 2.14 to 0.20, p=0.02, I 2 =79, N=4, n =103), mirtazapine augmentation therapy in patients primarily treated with SGAs was marginally superior to placebo for overall symptoms (S.M.D.= 1.31, CI 2.82 to 0.20, p=0.09, I 2 =90, N=4, n =105) and response rate (RR = 0.59, p=0.07, I 2 =60, N=3, n=80). Conversely, mirtazapine augmentation therapy improved both overall (S.M.D.= 0.90, CI 1.34 to 0.46, p<0.0001, I 2 =0, N= 3, n = 89) and negative symptoms (S.M.D.= 1.24, CI 1.94 to 0.87, p < , I 2 =0, N=2, n=69) compared with placebo groups in patients primarily treated with FGAs. Results of tolerability and side-effects There were no significant differences in discontinuation rate between NaSSAs and placebo treatments (discontinuation for the following reasons; all-cause: RR=1.19, CI , p =0.62, I 2 =0%, N=12, n=362, side-effects: RR=1.25, CI , p=0.69, I 2 =0%, N=11, n=332; Table 2). In addition, it was reported that there were no patients who received NaSSAs

5 Table 1. Study, patient and treatment characteristics of included double-blind randomized placebo-controlled trials Study Total (n) Patients (%) Diagnosis Duration Age (mean±s.d.) Male (%) Race (%) Drug n Dose (dose mg/d) Outcomes Concomitant drugs (%) Mirtazapine Abbasi et al. (2010) (Iran) 40 Chronic SZ (100). In-patients (100). Active phase of illness (PANSS total560 and PANSS negative 515). The patients did not receive AP for 1 wk prior to entering the trial or long acting APs at least 2 months before the study. DSM-IV-TR 8 wk Mir:33.35±6.42, ±7.51 Mir: 65.0, 70.0 Iranian (100) Mir +Ris 20 Mir:30, Ris:6 PBO+Ris 20 Ris:6 PANSS total: Mir>PBO. PANSS positive: Mir =PBO, PANSS negative: Mir>PBO, PANSS general: Mir =PBO Bip (NR), Overall mean Bip dosages (mg, mean±s.d.): Mir=104.04± , PBO = ± no. of days of Bip use (d, mean ±S.D.): Mir =16.38 ± 17.54, PBO =21.22 ± Berk et al. (2001) (South Africa) 30 SZ (100). In-patients (100). All participants received Hal (5 mg/d) DSM-IV and MINI 6 wk 29.5± NR Mir+Hal 15 Mir:30, Hal:5 PBO+Hal 15 Hal:5 PANSS total: Mir>PBO. PANSS positive: Mir =PBO, PANSS negative: Mir>PBO, PANSS general: Mir =PBO, HAMD: Mir =PBO Anti-CHO: Mir (40), PBO (86.7) Berk et al. (2009) (Australia) Industry Cho et al. (2011) (South Korea) 40 SZ (100). In-patients (NR) or out-patients (NR). All participants received SGA as usual [Clo (45), Que (21), Ris (18), Ola (9), Ari (6)] 21 SZ (100). Out-patients (100). All participants received Ris and CGI-S54. MINI 6 wk 36.8± NR Mir+SGA 20 Mir:30, SGA (Ris eq) =7.10 ± 3.29 DSM-IV 8 wk Mir:35.08±13.58, 36.44± 9.57 Mir: 45.4, 55.6 Korean (100%) PBO+SGA 20 SGA (Ris eq) =6.33 ±3.54 Mir +Ris 12 Mir:30, Ris: 3±1.94 PBO + Ris 9 Ris: 4.22 ± 1.83 PANSS positive: Mir =PBO, PANSS negative: Mir=PBO, PANSS general: Mir =PBO, HAMD: Mir =PBO PANSS total: Mir =PBO. PANSS positive: Mir =PBO, PANSS negative: Mir>PBO, PANSS general: Mir =PBO Benz (NR) BTP: Mir (55), PBO (78), Benz: Mir (67), PBO (87), Pro (NR) NaSSAs for schizophrenia 347

6 Table 1. (Cont.) Study Mirtazapine Joffe et al. (2009) (Finland) Total (n) Patients (%) Diagnosis Duration 40 SZ (97.5) and SA with depressive type. CGI-S54 (56 previous weeks). The patients had to receive 51 FGAs [5400 mg CHL eq, unchanged for 56 previous weeks (8 wk for depot FGAs)]. In-patients (Mir= 55%, PBO=36.8). Number of patients: Hal=14, Tri=13, Hal-D =10, Flu-D =8, Lev =6, CPT =5, Zuc-D =5, Zuc = 4, FLP=2, PRZ =2, Sul =1. Age (mean±s.d.) DSM-IV-TR 6 wk Mir:43.40±9.24, 48.21± 9.68 Male (%) Race (%) Drug n Mir: 55.0, 47.4 Dose (dose mg/d) NR Mir +FGA 20 Mir:30, FGA (CHL eq) = ± PBO+FGA 20 FGA (CHL eq) = ± Outcomes PANSS total: Mir =PBO. PANSS positive: Mir>PBO, PANSS negative: Mir>PBO, PANSS general: Mir =PBO, CDSS: Mir =PBO Concomitant drugs (%) Benz (NR) 348 T. Kishi and N. Iwata Poyurovsky (2003a) (Israel) 26 SZ (100). In-patients (100). All participants had mild akathisia (BAS52), and received FGAs (Hal=5 15 mg/d, Per=8 24 mg/d). DSM-IV 5 d Mir: 31.8±10.9, 29.1±9.9 Mir: 38.5, 61.5 NR Mir +FGA 13 Mir:15, FGA: PBO + FGA 13 FGA: PANSS: Mir=PBO, HAMD: Mir = PBO NR Zoccali et al. (2004) (Italy) 24 SZ. All patients had demonstrated persistent negative symptoms despite an adequate trial of Clo (Clo mg/d for at least 1 yr) DSM-IV 8 wk Mir:30.7±6.5, 33.4±9.0 Mir: 50.0, 70.0 NR Mir +Clo 12 Mir:30, Clo =320 ± PBO + Clo 12 Clo = 325 ± BPRS: Mir>PBO, SAPS: Mir =PBO, SANS: Mir>PBO, BPRS depression: Mir =PBO NR Mianserin Hayashi et al. (1997) (Japan) 26 SZ. Age550 yr and duration of illness 510 yr. Patients had moderate to severe negative symptoms and tardive dyskinesia and received FGA. DSM-III-TR 5 wk Mia:64.6±7.8, 59.9±9.3 Mia: 61.5, 53.8 Japanese (100) Mia +FGA 13 Mia: (15.8 +/ 6.1) [flexible], FGA(CHL eq) =492 ± 280 BPRS: Mia = PBO, BPRS positive: Mia =PBO, SANS: Mia>PBO NR PBO+FGA 13 FGA (CHL eq) =740 ± 531

7 Mianserin Miodownik et al. (2006) (Israel) 37 SZ (67.6) and SA. In-patients (100). All participants had mild akathisia (BAS52) DSM-IV 5 d Mia:39.1±13.0, 43.8±13.0 Mia: 60.0, 52.9 NR Mia +AP 20 Mia: 15, SGA (40%), FGA (60%) BPRS: Mia>PBO TPH: Mia (20), PBO (17.6) PBO + AP 17 SGA(35.3%), FGA (64.7%) NR Mia +FGA 15 Mia: 15, FGA Poyurovsky et al. (1999) (Israel) 30 SZ (53.3%), SA (16.7%) and SF (30%). All participants were in-patients, had mild akathisia (BAS52), and received FGA (Hal, Per, Flu) 30 SZ (100). In-patients (100) (12 36 months). All participants received FGA (Hal (50), CHL (40), Per (10)). DSM-IV 5 d Mia:30.1±8.5, 29.3±10.0 Mia: 66.7, 53.3 PBO+FGA 15 FGA BPRS: Mia>PBO, HAMD: Mia = PBO Anti-CHO (TPH and Bip): Mir (46.7), PBO (46.7), Benz: Mir (53.3), PBO (66.7), Poyurovsky (2003b) (Israel) DSM-IV 4 wk Mia:42.5±12.9, 45.5± NR Mia +FGA 15 Mia: 15, FGA PBO+FGA 15 FGA SAPS: Mia =PBO, SANS: Mia =PBO, HAMD: Mia = PBO Anti-CHO (TPH and Bip): Mir (93.3), PBO (93.3), Benz: Mir (66.7), PBO (53.3), VAL: Mir (20), PBO (13.3), THP: Mir (55.6), PBO (55.6), Pro: only PBO (22.2) Shiloh (2002) (Israel) 18 Treatment-resistant SZ (100). In-patients (100). Failed response at least 3 AP, and received FGA (Hal (50), Per (50). DSM-IV 6 wk Mia:32.8±9.0, 42.6±7.3 Mia: 55.6, 66.7 NR Mia +FGA 9 Mia: 30, FGA (CHL eq) =444.4 ± BPRS: Mia>PBO, SAPS: Mia =PBO, SANS: Mia =PBO, HAMD: Mia =PBO PBO+FGA 9 FGA (CHL eq) =566.7 ± Anti-CHO, Anticholinergic drugs; AP, antipsychotic; Ari, aripiprazole; BAS, Barnes Akathisia Rating Scale; Benz, benzodiazepines; BTP, benztropine; Bip, biperiden; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression of Severity; CDSS, Calgary Depression Scale for Schizophrenia; CPT, chlorprotixene; CHL eq, chlorpromazine equivalent; Clo, clozapine; DSM, Diagnostic and Statistical Manual of Mental Disorders; FGA, first generation antipsychotic; FLP, flupentixol; Flu, fluphenazine; Flu-D, fluphenazine decanoate; Hal, haloperidol; Hal-D, haloperidol decanoate; HAMD, Hamilton Rating Scale for Depression; Lev, levomepromazine; MINI, Mini-International Neuropsychiatric Interview; Mia, mianserin; Mir, mirtazapine; MD, mood stabilizer; NR, not reported; Ola, olanzapine; PANSS, Positive and Negative Syndrome Scale; PRZ, periciazine; Per, perphenazine; PBO, placebo; Pro, propranolol; Que, quetiapine; Ris, risperidone; SA, schizoaffective disorder; SAPS, Scales for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms; SF, schizophreniform disorder; SGA, second generation antipsychotic; SZ, schizophrenia; Sul, sulpiride; Tri, trifluoperazine; THP, trihexyphenidyl; VAL, valproic acid; Zuc, zuclopentixol; Zuc-D, zuclopentixol decanoate. NaSSAs for schizophrenia 349

8 350 T. Kishi and N. Iwata Table 2. NaSSAs vs. placebo, efficacy and discontinuation Outcome NaSSAs N n I 2 S.M.D. 95% CI p Overall symptoms Mirtazapine to Mianserin to Combined to Positive symptoms Mirtazapine to Mianserin to Combined to Negative symptoms Mirtazapine to Mianserin to Combined to PANSS general subscale scores Mirtazapine to Depressive symptoms Mirtazapine to Mianserin to Combined to Clinical Global Impression-Severity Mirtazapine 1 39 NA to Mianserin to Combined to NaSSAs N n I 2 RR 95% CI p Response rate for psychopathology Mirtazapine Mianserin Combined Discontinuation due to all cause Mirtazapine Mianserin Combined Discontinuation due to side-effect Mirtazapine Mianserin NA Combined NaSSAs, Noradrenergic and specific serotonergic antidepressants; N, number of studies; n, number of patients; S.M.D., standardized mean difference; CI, confidence intervals; PANSS, Positive and Negative Syndrome Scale; NA, not applicable; RR, risk ratio. p values<0.05 are shown in bold. who developed worsening psychosis during the study and dropped out from the study because of inefficacy or relapse. Although we conducted meta-analyses on seven side-effects (at least one side-effect, dizziness/orthostatic hypotension, drowsiness/sedation/somnolence, headache, psychosis exacerbation/worsening of schizophrenia, tremor/parkinsonism), we found only significant differences in drowsiness/sedation/somnolence between NaSSAs and the placebo treatment group (RR=3.52, CI , p=0.002, I 2 =0%, NNH =6, p= 0.01, N =8, n = 209; Table 3; Supplementary Fig. S3). For individual NaSSAs, both mirtazapine and mianserin were associated with higher risk drowsiness/ sedation/somnolence compared with placebo (mirtazapine: RR=5.46, p=0.02, NNH =5, p= N=3, n=86; mianserin: RR=2.91, p=0.03, NNH =n.s., N=5, n =123; Table 3; Supplementary Fig. S3). Regarding akathisia and EPS, the patients who received NaSSAs had lower SAS and BAS scores than patients who received placebo (BAS-objective: S.M.D.= 1.19, p < ; BAS-distress: S.M.D.= 1.22, p < ; BAS-global: S.M.D.= 1.48, p < ; SAS: S.M.D.= 0.56, p = 0.01; Table 4). Discussion This is the first systematic review and meta-analysis to focus on the efficacy and tolerability of NaSSA augmentation therapy in patients with schizophrenia. While NaSSA augmentation therapy did not differ from placebo regarding positive symptoms and PANSS general subscale scores, NaSSAs (especially mirtazapine) augmentation therapy significantly exhibited better overall and negative symptoms than placebo with large effect size (S.M.D.: overall symptoms

9 NaSSAs for schizophrenia 351 Table 3. NaSSAs vs. placebo, side-effect Side-effect NaSSAs N n I 2 RR 95% CI p At least one side-effect Mirtazapine Mianserin 1 37 NA NA Combined Dizziness/orthostatic hypotension Mirtazapine 1 40 NA Mianserin Combined Drowsiness/sedation/somnolence Mirtazapine Mianserin Combined Headache Mirtazapine Mianserin 1 37 NA NA Combined Psychosis exacerbation/worsening of schizophrenia Mianserin 3 93 NA NA Tremor/Parkinsonism Mirtazapine Mianserin 2 55 NA Combined NaSSAs, Noradrenergic and specific serotonergic antidepressants; N, number of studies; n, number of patients; NA, not applicable; S.M.D., standardized mean difference; CI, confidence intervals; RR, risk ratio. p values<0.05 are shown in bold. Table 4. NaSSAs vs. placebo, akathisia and extrapyramidal symptoms Outcome NaSSAs N n I 2 S.M.D. 95% CI p BAS-objective Mirtazapine 1 20 NA to Mianserin to 0.58 < Combined to 0.71 < BAS-subjective Mirtazapine 1 20 NA to Mianserin to Combined to BAS-distress Mirtazapine 1 20 NA to Mianserin to 0.83 < Combined to 0.74 < BAS-global Mirtazapine 1 20 NA to Mianserin to 0.91 < Combined to 0.98 < SAS Mirtazapine 1 36 NA to Mianserin to Combined to NaSSAs N n I 2 RR 95% CI P Response rate for akathisia Mirtazapine 1 26 NA Mianserin Combined < BAS, Barnes Akathisia Scale; SAS, Simpson Angus Scale; N, number of studies; n, number of patients; NA, not applicable; S.M.D., standardized mean difference; CI, confidence intervals; RR, risk ratio. p values<0.05 are shown in bold.

10 352 T. Kishi and N. Iwata = 0.75, negative symptoms = 0.88) and were also well tolerated compared with placebo (no significant differences in discontinuation due to all-cause as well as side-effect). We also detected marginal differences in depressive symptoms (p = 0.09) between NaSSA augmentation therapy (especially mirtazapine) and placebo. Because the included studies in the metaanalysis were small, the non-significant results could be because of low statistical power (i.e. type II error). NaSSA augmentation therapy did not produce worsening of schizophrenia compared with placebo in all included studies in the meta-analysis. From the above results, NaSSA augmentation therapy may be beneficial for the treatment of schizophrenia with regard to overall as well as negative symptoms. Many reports insist that SGAs show efficacy in treating negative symptoms and that this is an important difference between SGAs and FGAs. However, Leucht et al. (2009a) reported that, although amisulpride, clozapine, olanzapine and risperidone showed greater efficacy than FGAs in the treatment of negative symptoms, aripiprazole, quetiapine, sertindole, ziprasidone and zotepine were not superior to FGAs in the treatment of negative symptoms. However, since clozapine and olanzapine have a high risk of cardiometabolic disorder (Correll et al., 2009, 2011), clinicians have to use these antipsychotics with caution. Risperidone is also reported to have a risk for obesity (Correll et al., 2009, 2011) and hyperprolactinemia (Kishi et al., 2012; Moteshafi and Stip, 2012). Recently, it has been recommended that the antipsychotics that have less of a risk of side-effects, such as aripiprazole, should be selected for the treatment of schizophrenia (Buchanan et al., 2010). However, aripiprazole does not benefit the treatment of negative symptoms compared with FGAs (Leucht et al., 2009a). The results of our meta-analysis may suggest that NaSSAs (especially mirtazapine) enhance the efficacy (especially negative symptoms) of aripiprazole. The EPS and akathisia also lead to the discontinuation of antipsychotic treatment of schizophrenia (Kane et al., 2009, 2010; Rummel-Kluge et al., 2012). Risperidone is also reported to be associated with more use of anti-parkinson medication than clozapine, olanzapine, quetiapine and ziprasidone and has a risk of EPS (Rummel-Kluge et al., 2012). Aripiprazole is also reported to produce more akathisia than olanzapine and was associated more with the use of anti-parkinson medication than olanzapine (Rummel- Kluge et al., 2012). On the other hand, while blonanserin, which is available for the treatment of schizophrenia only in Japan and Korea, is more efficacious for negative symptoms than FGA, and has lower risk of cardio-metabolic risk, it also produces more akathisia than risperidone (Kishi et al., 2012). Although EPS data were limited, and most studies used anticholinergic drugs in the current metaanalysis, our results show that NaSSAs seem to benefit the treatment of akathisia and EPS compared with placebo. The results of our meta-analysis may suggest that NaSSAs cover these deficits (akathisia and EPS) of aripiprazole and blonanserin. Larger trials are needed to extend these findings and to determine if NaSSAs influence the success of aripiprazole or blonanserin treatment in schizophrenia. Since there were few studies that reported the efficacy of NaSSA augmentation therapy for cognitive function in schizophrenia patients, we were unable to perform a meta-analysis. However, Cho et al. (2011) reported that mirtazapine augmentation was superior to placebo management in ameliorating some cognitive impairment (vocabulary test and immediate memory). Stenberg et al. (2010) also reported that mirtazapine augmentation was superior to placebo in areas of visual-spatial ability and general mental speed/attention control. Moreover, not only speed but also accuracy of performance improved in patients with mianserin augmentation, when compared with the placebo group (Poyurovsky et al., 2003b). Thus, these results suggest that NaSSAs have cognitiveenhancing effects in patients with schizophrenia. The results of this study need to be interpreted within its limitations. The main limitation is the small number of studies included. Future investigations of the therapeutic potential of NaSSAs should include a larger sample size. In particular, there were only four RCTs of SGAs included in the meta-analysis (two risperidone trials, one clozapine trial, one mixed SGA trial). It remains unclear which antipsychotic should be used in association with NaSSA. The second limitation is that patients with schizophrenia have been reported to have poor adherence to medication regimens, making it difficult to firmly establish the effectiveness of pharmacological interventions in this population (Lopez-Munoz and Rubio, 2011). Finally, two of the 12 trials included in this meta-analysis were short in duration (5 d). Future research should investigate long-term efficacy and generate more safety data. In conclusion, our results indicate that NaSSA (especially mirtazapine) augmentation therapy improves overall and negative symptoms in patients with schizophrenia, and is well tolerated. Although EPS data were limited, our results show that NaSSAs seem to benefit the treatment of akathisia and EPS compared with placebo. Because the included

11 NaSSAs for schizophrenia 353 studies were small, results should be treated with caution. Acknowledgement We thank Seetal Dodd, MD (The University of Melbourne) for providing additional information for the study. Statement of Interest Dr Kishi has received speaker s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, Yoshitomi, Otsuka, Meiji, Shionogi, Tanabe- Mitsubishi, Novartis and Pfizer. Dr Iwata has received speaker s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis and Pfizer. Supplementary material For supplementary material accompanying this paper, visit References Abbasi SH, Behpournia H, Ghoreshi A, Salehi B, Raznahan M, Rezazadeh SA, Rezaei F, Akhondzadeh S (2010) The effect of mirtazapine add on therapy to risperidone in the treatment of schizophrenia: a double-blind randomized placebo-controlled trial. Schizophr Res 116: Addington D, Addington J, Schissel B (1990) A depression rating scale for schizophrenics. Schizophr Res 3: Andreasen NC (1982) Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry 39: Andreasen NC (1985) Positive vs. negative schizophrenia: a critical evaluation. Schizophr Bull 11: Barnes TR (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154: Berk M, Ichim C, Brook S (2001) Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol 16: Berk M, Gama CS, Sundram S, Hustig H, Koopowitz L, D Souza R, Malloy H, Rowland C, Monkhouse A, Monkhouse A, Bole F, Sathiyamoorthy S, Piskulic D, Dodd S (2009) Mirtazapine add-on therapy in the treatment of schizophrenia with atypical antipsychotics: a double-blind, randomised, placebo-controlled clinical trial. Hum Psychopharmacol 24: Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W, Schizophrenia Patient Outcomes Research T (2010) The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 36: Cho SJ, Yook K, Kim B, Choi TK, Lee KS, Kim YW, Lee JE, Suh S, Yook KH, Lee SH (2011) Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 35: Cohn LD, Becker BJ (2003) How meta-analysis increases statistical power. Psychol Methods 8: Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK (2009) Cardiometabolic risk of secondgeneration antipsychotic medications during first-time use in children and adolescents. JAMA 302: Correll CU, Lencz T, Malhotra AK (2011) Antipsychotic drugs and obesity. Trends Mol Med 17: Croom KF, Perry CM, Plosker GL (2009) Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS drugs 23: DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: Foussias G, Remington G (2010) Negative symptoms in schizophrenia: avolition and Occam s razor. Schizophr Bull 36: Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG (2007) Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 64: Goldberg TE, Keefe RS, Goldman RS, Robinson DG, Harvey PD (2010) Circumstances under which practice does not make perfect: a review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies. Neuropsychopharmacology 35: Guy W, Bonato RR (1970) Manual for the ECDEU assessment battery, 2nd edn. Chevy Chase, MD, National Institute of Mental Health. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23: Hayashi T, Yokota N, Takahashi T, Tawara Y, Nishikawa T, Yano T, Furutani M, Fujikawa T, Horiguchi J, Yamawaki S (1997) Benefits of trazodone and mianserin for patients with late-life chronic schizophrenia and tardive dyskinesia: an add-on, double-blind, placebo-controlled study. Int Clin Psychopharmacol 12: Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: Joffe G, Terevnikov V, Joffe M, Stenberg JH, Burkin M, Tiihonen J (2009) Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial. Schizophr Res 108: Kane JM, Fleischhacker WW, Hansen L, Perlis R, Pikalov A III, Assuncao-Talbott S (2009) Akathisia:

12 354 T. Kishi and N. Iwata an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 70: Kane JM, Barnes TR, Correll CU, Sachs G, Buckley P, Eudicone J, McQuade R, Tran QV, Pikalov A III, Assuncao-Talbott S (2010) Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: a post-hoc analysis of pooled data from short- and long-term aripiprazole trials. J Psychopharmacol 24: Kay SR, Opler LA, Lindenmayer JP (1989) The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry (Suppl.)7: Kishi T, Moriwaki M, Kawashima K, Okochi T, Fukuo Y, Kitajima T, Furukawa O, Naitoh H, Fujita K, Iwata N (2010) Investigation of clinical factors influencing cognitive function in Japanese schizophrenia. Neurosci Res 66: Kishi T, Matsuda Y, Nakamura H, Iwata N (2012) Blonanserin for schizophrenia: systematic review and meta-analysis of double-blind, randomized, controlled trials. J Psychiatr Res 47: Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009a) Second-generation vs. first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373: Leucht S, Komossa K, Rummel-Kluge C, Corves C, Hunger H, Schmid F, Asenjo Lobos C, Schwarz S, Davis JM (2009b) A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 166: Liebman JM, Lovell RA, Braunwalder A, Stone G, Bernard P, Barbaz B, Welch J, Kim HS, Wasley JW, Robson RD (1983) CGS 7525A, a new, centrally active alpha 2 adrenoceptor antagonist. Life Sci 32: Lopez-Munoz F, Rubio G (2011) Many people show poor adherence to their initial antipsychotic after first hospitalisation with schizophrenia. Evid Based Ment Health 14:96. Milev P, Ho BC, Arndt S, Andreasen NC (2005) Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry 162: Miodownik C, Lerner V, Statsenko N, Dwolatzky T, Nemets B, Berzak E, Bergman J (2006) Vitamin B6 vs. mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study. Clin Neuropharmacol 29: Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535. Moteshafi H, Stip E (2012) Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia and affective disorders: a meta-analysis. Expert Opin Drug Saf 11: Niho T, Ito C, Shibutani Y, Hashizume H, Yamaguchi K (1986) Pharmacological properties of MO-8282, a novel antidepressant. Nihon yakurigaku zasshi Folia pharmacologica Japonica 88: Overall JE, Gorham DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: Pinder RM, van Delft AM (1983) Pharmacological aspects of mianserin. Acta Psychiatr Scand Suppl 302: Poyurovsky M, Shardorodsky M, Fuchs C, Schneidman M, Weizman A (1999) Treatment of neuroleptic-induced akathisia with the 5-HT2 antagonist mianserin. Double-blind, placebo-controlled study. Br J Psychiatry 174: Poyurovsky M, Epshtein S, Fuchs C, Schneidman M, Weizman R, Weizman A (2003a) Efficacy of low-dose mirtazapine in neuroleptic-induced akathisia: a double-blind randomized placebo-controlled pilot study. J Clin Psychopharmacol 23: Poyurovsky M, Koren D, Gonopolsky I, Schneidman M, Fuchs C, Weizman A, Weizman R (2003b) Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 13: Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Kissling W, Davis JM, Leucht S (2012) Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 38: Shiloh R, Zemishlany Z, Aizenberg D, Valevski A, Bodinger L, Munitz H, Weizman A (2002) Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia. Int Clin Psychopharmacol 17: Simpson GM, Angus JW (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 212: Singh SP, Singh V, Kar N, Chan K (2010) Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 197: Stenberg JH, Terevnikov V, Joffe M, Tiihonen J, Tchoukhine E, Burkin M, Joffe G (2010) Effects of add-on mirtazapine on neurocognition in schizophrenia: a double-blind, randomized, placebo-controlled study. Int Clin Psychopharmacol 13: Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, Furukawa TA (2011) Mirtazapine vs. other antidepressive agents for depression. Cochrane Database Syst Rev:CD Yamada K, Furukawa T (1991) Behavioral effects of a new antidepressant, setiptiline. Nihon yakurigaku zasshi Folia pharmacologica Japonica 97: Zoccali R, Muscatello MR, Cedro C, Neri P, La Torre D, Spina E, Di Rosa AE, Meduri M (2004) The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol 19:71 76.