Non-glutamatergic Clozapine Augmentation Strategies a Review and Meta-analysis

Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

Iris E. Sommer,

1Neuroscience Section of the University Medical Center Utrecht & Rudolf Magnus Institute for Neuroscience, Utrecht, the netherlands

*To whom correspondence should be addressed; tel: +31-88-7556370, fax: +31-88-7555443, e-mail: i.sommer@umcutrecht.nl

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Abstract

Background. When schizophrenia patients take insufficient response to clozapine, pharmacological augmentation is ofttimes applied. This meta-assay summarizes bachelor evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder. Methods. Only double-blind randomized controlled studies were included. Main event measure out was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g). Results. 20-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared subsequently outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on unmarried studies. Conclusions. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on unmarried studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (nevertheless) demonstrated to be superior to placebo.

Introduction

Although antipsychotic agents are constructive in the bulk of patients with schizophrenia, between one-5th and one-third of patients have little, if any, benefit from them.ane Treatment of these patients has remained a persistent public wellness problem every bit medication-resistant patients are frequently highly symptomatic,2 accept a severely reduced quality of life, and need extensive periods of hospital care.2 They as well require a unduly high amount of the full health costs for schizophrenia.3,four

The landmark trial of Kane et al5 demonstrated superior efficacy for clozapine over other antipsychotic agents for this subgroup of medication-resistant patients, a finding that has now consistently been replicated.6–8 In club to optimize clozapine therapy, several studies have evaluated the relationship between clozapine claret levels and therapeutic response. Clozapine levels above 350–450 μg/ml are shown to be associated with superior treatment response than lower levels (reviewed by Schultenine). Although clozapine is considered the most efficient antipsychotic agent in refractory patients, equally many equally 40%–seventy% of these patients attain only poor or partial response with information technology, even with acceptable blood levels of clozapine.v,ten–12 For these ultra-resistant patients, several treatment strategies tin be followed, including psychotherapy,xiii pharmacological augmentation,14 repetitive transcranial magnetic stimulation,15 or electroconvulsive therapy.sixteen Augmentation of clozapine with some other pharmacological substance is used frequently in clinical practice, despite the paucity of evidence that adding a second drug volition enhance antipsychotic properties.17–20 Some of the almost frequently prescribed augmentation components are lithium, sodium valproate, benzodiazepines, various selective serotonin reuptake inhibitors (SSRIs), risperidone, haloperidol, and aripiprazole.21 Since clinicians quite routinely plough to pharmacological augmentation strategies when facing clozapine-resistant schizophrenia patients, a critical evaluation of the efficacy of pharmacological agents in augmenting clozapine treatment response is warranted.

There are numerous reports available regarding augmentation strategies in patients with poor or partial response to clozapine. Augmentation with conventional or atypical antipsychotics,22,23 various antidepressants,24,25 lithium,26 sodium valproate,27 carbamazepine,28 novel anticonvulsants,29 dopamine agonists,30 glutamate receptor agonists,31 mazindol,32 and omega-3 fatty acids33 have all been described as clozapine adjuncts in the treatment of resistant symptoms. The available literature addressing different augmentation strategies in clozapine-resistant patients seems promising at first glance considering nigh reports advise that therapeutic benefits can be gained.14,34–36 However, well-nigh studies are case reports, retrospective chart reviews, and pocket-sized sampled uncontrolled trials. Such studies tend to produce a strong bias for positive results because negative reports in a instance or a small-scale sample are unlikely to exist reported and/or published.37,38 In addition, the specific therapeutic response cannot be distinguished from placebo effects in uncontrolled studies. Meanwhile, at that place are simply few randomized controlled trials (RCTs) available.

Perhaps as a result of the paucity of well-designed studies, proficient guidelines accept generally been reticent virtually augmentation strategies for clozapine-resistant patients.38,39 For example, the 2009 Schizophrenia Patient Outcomes Research Team has discussed adjunctive treatment strategies but argued that studies have failed to document sufficient efficacy to support a recommendation in patients with clozapine-resistant schizophrenia.40

Therefore, this study aims to review all double-blind randomized controlled studies available regarding the efficacy of pharmacological augmentation in clozapine-resistant patients, and perform meta-analyses on the efficacy of individual clozapine adjuncts when sufficient studies are available. Past quantitatively summarizing the literature on clozapine augmentation strategies, this review aims to assess the efficacy of the unlike clozapine augmentation strategies in reducing persistent positive and negative symptoms of schizophrenia.

Methods

Literature Search

This meta-analysis was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Argument.41 The protocol of the search strategy can be viewed online (http://www.stemmenpoliumcutrecht.nl/). An electronic search was performed using Medline, Embase, PsychInfo, National Institutes of Health, ClinicalTrials.gov, Cochrane Schizophrenia Group entries in PsiTri (http://psitri.stakes.fi), and the Cochrane Database of Systematic Reviews.

There were no year or language restrictions. The following basic search terms were used, both lonely and in combinations: 'schizophrenia,' 'clozapine,' 'resistant,' 'refractory,' and the names of the particular pharmacological components used for augmentation. Additionally, the reference lists of the retrieved manufactures and relevant review articles were examined for cross-references. When necessary, corresponding authors were contacted to provide full details of report outcomes or scores for subgroups of patients treated with clozapine.

Inclusion

Consensus on the studies included was reached on the footing of the following criteria:

Randomized, double-blind placebo-controlled studies of at least 2 weeks duration regarding clozapine augmentation by a second drug.
Patients included had a diagnosis of a schizophrenia spectrum disorder (schizophrenia, schizoaffective disorder, or psychotic disorder non otherwise specified), according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders 42 (DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, or International Classification of Diseases-9 or 10).
Patients were treated with a stable dose of clozapine for a minimum of iv weeks before the study started. The use of comedication was permitted if dosage had been without changes for four weeks prior to written report onset and during the study.
Studies reported sufficient information to compute common effect size statistics, ie, means and SDs, exact P, t, or z values (cf. Lipsey and Wilson43) or corresponding authors could supply these data upon asking.

Crossover studies were not excluded in society to obtain as much information as possible.

Outcome Measures

The chief outcome measure was the mean change in total score on the Positive and Negative Syndrome Calibration44 (PANSS) or the Cursory Psychiatric Rating Scale45 (BPRS). Secondary consequence measures included positive and negative symptom subscores of the PANSS or the BPRS or scores on the Calibration for the Assessment of Positive Symptoms46 and the Calibration for the Assessment of Negative Symptoms47. Patient data of the last observation carried forrard were used for analysis. If studies did not provide these data and they could not exist received from the respective authors, but the data of completers were used. Where possible, side effects were evaluated by comparison scores on the diverse side furnishings scales, weight, torso mass index, hypersalivation, and prolactin claret levels between the augmentation and the placebo group.

Statistical Analyses

2 reviewers independently extracted data from the articles, whatever disagreements were resolved by consensus. Consequence sizes were calculated for the mean differences (placebo vs augmentation) of the change score (end of treatment minus baseline) means and SDs. Modify scores were used instead of pretreatment and posttreatment scores in order to avoid overestimation of the true outcome size because of the pre-postal service treatment correlation.48 All effect sizes were calculated twice independently from the original manufactures to check for errors. When more than ane RCT on a particular augmentation strategy was present, effect sizes of studies were pooled in meta-analyses to obtain a combined weighted effect size for chief and secondary outcome measures. Hedges's k was used to quantify the mean weighted effect sizes of combined studies using a random model.49 A homogeneity statistic, I ², was calculated to test whether the studies could be taken together to share a mutual population effect size.50 Loftier heterogeneity (ie, I ² 50% or higher) indicates heterogeneity of the individual written report consequence sizes, which poses a limitation to a reliable interpretation of the results. Values of I ² between xxx% and 50% were considered moderate. Outliers, defined as effect sizes that deviate more than 2 SDs from the mean weighted result size, were removed from analyses. Outcome sizes with a P < .05 were considered pregnant. All effect sizes were computed using Comprehensive Meta Assay Version 2.0.51

Results

Figure 1 reflects the literature search that resulted in 29 included RCTs.xviii,19,23,24,29,31,52–73 Information of a total of 1066 schizophrenia and schizoaffective patients were analyzed. Of the 29 included studies, v studies29,52–55 had a crossover design. Double-blind RCTs that could not exist included are listed in online Supplementary Data (tabular array i) with the reason for exclusion.

Fig. 1.

Preferred reporting items for systematic reviews and meta-analyses flow diagram of the literature search.

Antiepileptic Medication

Eight studies applying antiepileptic drugs as clozapine augmentation were included, which are summarized in online supplementary material, for table 2.

Lamotrigine.

For total symptom severity, lamotrigine showed superior efficacy to placebo, but heterogeneity was high. Figure 2 plots the individual effect sizes per written report regarding total symptom score from the PANSS or BPRS rating scales. The study by Zoccali et al56 was considered an outlier and therefore excluded from assay. Afterward exclusion, the hateful weighted effect size was no longer meaning and studies were homogeneous.

Fig. 2.

Meta-analysis of lamotrigine augmentation for total symptom score [positive and negative syndrome scale (PANSS)/brief psychiatric rating scale (BPRS)] including outlier.56

Concerning positive symptom severity, the meta-analysis showed a tendency toward superiority of lamotrigine over placebo in reducing positive symptoms, and heterogeneity was moderate. Again, the study by Zoccali et al56 was an outlier. Subsequently exclusion, the trend disappeared and heterogeneity was nil.

Regarding negative symptom scores, the meta-assay showed no significant difference between lamotrigine and placebo, and heterogeneity was high. Again, Zoccali et al56 was an outlier. After exclusion, Hedges'southward thou decreased and heterogeneity disappeared.

Topiramate.

The iii RCTs55,57,58 on topiramate every bit clozapine augmentation strategy, including 89 patients, showed a trend toward superior effect over placebo in reducing total symptom severity, but the data were heterogeneous. The report past Afshar et al57 was considered an outlier. Later removal, the trend disappeared.

Fig. iii.

Issue sizes of studies comparing topiramate augmentation to placebo (total positive and negative syndrome scale scores) including outlier.57

Regarding positive symptoms as measured by the subscale of the PANSS, topiramate was superior to placebo, but studies were heterogeneous. The report by Afshar et al57 was considered an outlier. After exclusion, the significant effect disappeared and heterogeneity decreased. The effect of topiramate on severity of negative symptoms was not pregnant and studies were heterogeneous. However, the written report past Afshar was non considered an outlier for this assay. Statistical findings of these meta-analyses are summarized in table 1.

Table 1.

Summary of Augmentation Strategies and Their (Mean) Standardized Differences.

Augmentation Strategy	Studies (N)	Subjects (N)	PANSS/BPRS Total			Positive Subscores			Negative Subscores
Augmentation Strategy	Studies (N)	Subjects (N)	Hedges'south g	95% CI	I ^two (%)	Hedges's m	95% CI	I ² (%)	Hedges's thousand	95% CI	I ² (%)
Antiepileptics	7	189
Lamotrigine	5	143	0.53	0.03–1.04	60	0.38	−0.02 to 0.78	39	0.41	−0.13 to 0.94	64
Minus outlier	4	92	0.27	−0.10 to 0.65	0	0.15	−0.22 to 0.52	0	0.12	−0.25 to 0.49	0
Topiramate	3	89	0.75	−0.05 to 1.56	69	0.63	0.03–1.23	47	0.66	−0.17 to i.v	71
Minus outlier	2	57	0.38	−0.13 to 0.89	0	0.39	−0.24 to ane.01	25
Antidepressants	4	129
Citalopram	1	61	0.81	0.30–i.33		0.28	−0.22 to 0.79		0.81	0.30–1.33
Fluoxetine	1	33	No data			0.12	−0.55 to 0.79		0.nineteen	−0.48 to 0.86
Mirtazapine	2	35	two.91	−2.69 to 8.51	96	0.04	−0.59 to 0.67	0	1.xx	−0.25 to 2.66	76
Antipsychotics	10	548
Amisulpride	1	xx	0.13	−0.48 to 0.74		0.11	−0.50 to 0.72		0.21	−0.40 to 0.82
Aripiprazole	2	268	0.12	−0.12 to 0.36	0	0.22	−0.02 to 0.46	0	0.37	−0.19 to 0.93	74
Haloperidol	1	6	−0.15	−ane.51 to one.21		0.26	−ane.11 to ane.62		−0.31	−i.68 to i.06
Risperidone	5	226	0.18	−0.21 to 0.57	53	0.09	−0.24 to 0.74	56	0.22	−0.fourteen to 0.57	43
Sulpiride	1	28	0.83	0.07–1.59		0.77	0.02–1.52		0.76	0.01–one.51
Glutamatergics	7	137
CX516	1	18	ane.35	0.32–two.38		0.20	−0.74 to 1.14		1.43	0.38–2.46
D-cycloserine	1	11	No data			No data			−0.76	−1.59 to 0.08
D-serine	one	xx	No data			0.40	−0.45 to 1.24		0.33	−0.52 to 1.17
Glycine	3	68	−0.16	−0.62 to 0.30	0	−0.36	−1.19 to 0.46	67	−0.14	−0.60 to 0.32	0
Sarcosine	ane	xx	−0.21	−1.06 to 0.63		−0.07	−0.91 to 0.77		−0.07	−0.91 to 0.77

Augmentation Strategy	Studies (N)	Subjects (N)	PANSS/BPRS Total			Positive Subscores			Negative Subscores
Augmentation Strategy	Studies (N)	Subjects (N)	Hedges's m	95% CI	I ⁱⁱ (%)	Hedges'south one thousand	95% CI	I ² (%)	Hedges's one thousand	95% CI	I ² (%)
Antiepileptics	7	189
Lamotrigine	5	143	0.53	0.03–1.04	60	0.38	−0.02 to 0.78	39	0.41	−0.thirteen to 0.94	64
Minus outlier	iv	92	0.27	−0.10 to 0.65	0	0.15	−0.22 to 0.52	0	0.12	−0.25 to 0.49	0
Topiramate	iii	89	0.75	−0.05 to 1.56	69	0.63	0.03–1.23	47	0.66	−0.17 to one.five	71
Minus outlier	2	57	0.38	−0.13 to 0.89	0	0.39	−0.24 to one.01	25
Antidepressants	iv	129
Citalopram	1	61	0.81	0.xxx–1.33		0.28	−0.22 to 0.79		0.81	0.30–ane.33
Fluoxetine	1	33	No data			0.12	−0.55 to 0.79		0.19	−0.48 to 0.86
Mirtazapine	two	35	2.91	−2.69 to 8.51	96	0.04	−0.59 to 0.67	0	one.20	−0.25 to two.66	76
Antipsychotics	10	548
Amisulpride	one	xx	0.13	−0.48 to 0.74		0.11	−0.50 to 0.72		0.21	−0.forty to 0.82
Aripiprazole	2	268	0.12	−0.12 to 0.36	0	0.22	−0.02 to 0.46	0	0.37	−0.19 to 0.93	74
Haloperidol	1	half-dozen	−0.xv	−1.51 to 1.21		0.26	−i.11 to 1.62		−0.31	−one.68 to 1.06
Risperidone	5	226	0.xviii	−0.21 to 0.57	53	0.09	−0.24 to 0.74	56	0.22	−0.14 to 0.57	43
Sulpiride	one	28	0.83	0.07–1.59		0.77	0.02–1.52		0.76	0.01–i.51
Glutamatergics	7	137
CX516	one	18	1.35	0.32–2.38		0.20	−0.74 to ane.14		1.43	0.38–two.46
D-cycloserine	one	11	No data			No data			−0.76	−1.59 to 0.08
D-serine	1	20	No data			0.40	−0.45 to i.24		0.33	−0.52 to i.17
Glycine	3	68	−0.xvi	−0.62 to 0.30	0	−0.36	−1.19 to 0.46	67	−0.14	−0.lx to 0.32	0
Sarcosine	one	20	−0.21	−1.06 to 0.63		−0.07	−0.91 to 0.77		−0.07	−0.91 to 0.77

Note: Significant effects are indicated in assuming. PANSS, Positive and Negative Syndrome Scale; BPRS, Cursory Psychiatric Rating Calibration.

Tabular array 1.

Summary of Augmentation Strategies and Their (Hateful) Standardized Differences.

Augmentation Strategy	Studies (N)	Subjects (Northward)	PANSS/BPRS Total			Positive Subscores			Negative Subscores
Augmentation Strategy	Studies (N)	Subjects (Northward)	Hedges's g	95% CI	I ^two (%)	Hedges's thousand	95% CI	I ⁱⁱ (%)	Hedges's one thousand	95% CI	I ⁱⁱ (%)
Antiepileptics	vii	189
Lamotrigine	5	143	0.53	0.03–ane.04	sixty	0.38	−0.02 to 0.78	39	0.41	−0.thirteen to 0.94	64
Minus outlier	4	92	0.27	−0.10 to 0.65	0	0.15	−0.22 to 0.52	0	0.12	−0.25 to 0.49	0
Topiramate	iii	89	0.75	−0.05 to 1.56	69	0.63	0.03–one.23	47	0.66	−0.17 to ane.5	71
Minus outlier	ii	57	0.38	−0.13 to 0.89	0	0.39	−0.24 to 1.01	25
Antidepressants	four	129
Citalopram	i	61	0.81	0.30–1.33		0.28	−0.22 to 0.79		0.81	0.thirty–1.33
Fluoxetine	one	33	No data			0.12	−0.55 to 0.79		0.19	−0.48 to 0.86
Mirtazapine	2	35	2.91	−2.69 to viii.51	96	0.04	−0.59 to 0.67	0	one.20	−0.25 to 2.66	76
Antipsychotics	ten	548
Amisulpride	1	xx	0.13	−0.48 to 0.74		0.11	−0.fifty to 0.72		0.21	−0.twoscore to 0.82
Aripiprazole	two	268	0.12	−0.12 to 0.36	0	0.22	−0.02 to 0.46	0	0.37	−0.xix to 0.93	74
Haloperidol	1	half-dozen	−0.15	−1.51 to 1.21		0.26	−1.11 to 1.62		−0.31	−ane.68 to 1.06
Risperidone	5	226	0.18	−0.21 to 0.57	53	0.09	−0.24 to 0.74	56	0.22	−0.fourteen to 0.57	43
Sulpiride	one	28	0.83	0.07–1.59		0.77	0.02–1.52		0.76	0.01–1.51
Glutamatergics	7	137
CX516	1	18	i.35	0.32–two.38		0.xx	−0.74 to 1.14		1.43	0.38–2.46
D-cycloserine	i	11	No data			No data			−0.76	−1.59 to 0.08
D-serine	1	20	No data			0.40	−0.45 to i.24		0.33	−0.52 to 1.17
Glycine	3	68	−0.sixteen	−0.62 to 0.30	0	−0.36	−1.19 to 0.46	67	−0.14	−0.lx to 0.32	0
Sarcosine	i	20	−0.21	−ane.06 to 0.63		−0.07	−0.91 to 0.77		−0.07	−0.91 to 0.77

Augmentation Strategy	Studies (N)	Subjects (N)	PANSS/BPRS Total			Positive Subscores			Negative Subscores
Augmentation Strategy	Studies (N)	Subjects (N)	Hedges'southward k	95% CI	I ² (%)	Hedges's thou	95% CI	I ² (%)	Hedges'southward chiliad	95% CI	I ² (%)
Antiepileptics	7	189
Lamotrigine	5	143	0.53	0.03–i.04	60	0.38	−0.02 to 0.78	39	0.41	−0.xiii to 0.94	64
Minus outlier	4	92	0.27	−0.10 to 0.65	0	0.15	−0.22 to 0.52	0	0.12	−0.25 to 0.49	0
Topiramate	3	89	0.75	−0.05 to 1.56	69	0.63	0.03–1.23	47	0.66	−0.17 to one.5	71
Minus outlier	2	57	0.38	−0.13 to 0.89	0	0.39	−0.24 to one.01	25
Antidepressants	four	129
Citalopram	i	61	0.81	0.30–ane.33		0.28	−0.22 to 0.79		0.81	0.30–i.33
Fluoxetine	i	33	No data			0.12	−0.55 to 0.79		0.19	−0.48 to 0.86
Mirtazapine	2	35	ii.91	−2.69 to 8.51	96	0.04	−0.59 to 0.67	0	one.20	−0.25 to 2.66	76
Antipsychotics	10	548
Amisulpride	1	xx	0.13	−0.48 to 0.74		0.xi	−0.50 to 0.72		0.21	−0.xl to 0.82
Aripiprazole	ii	268	0.12	−0.12 to 0.36	0	0.22	−0.02 to 0.46	0	0.37	−0.xix to 0.93	74
Haloperidol	1	6	−0.xv	−one.51 to 1.21		0.26	−1.xi to 1.62		−0.31	−1.68 to one.06
Risperidone	5	226	0.xviii	−0.21 to 0.57	53	0.09	−0.24 to 0.74	56	0.22	−0.14 to 0.57	43
Sulpiride	one	28	0.83	0.07–1.59		0.77	0.02–ane.52		0.76	0.01–1.51
Glutamatergics	vii	137
CX516	1	18	1.35	0.32–2.38		0.20	−0.74 to 1.14		ane.43	0.38–ii.46
D-cycloserine	ane	11	No information			No data			−0.76	−ane.59 to 0.08
D-serine	i	20	No information			0.40	−0.45 to ane.24		0.33	−0.52 to 1.17
Glycine	3	68	−0.16	−0.62 to 0.30	0	−0.36	−1.nineteen to 0.46	67	−0.14	−0.60 to 0.32	0
Sarcosine	1	twenty	−0.21	−1.06 to 0.63		−0.07	−0.91 to 0.77		−0.07	−0.91 to 0.77

Note: Significant effects are indicated in bold. PANSS, Positive and Negative Syndrome Scale; BPRS, Brief Psychiatric Rating Scale.

Antidepressants

Four studies apropos the efficacy of antidepressants as clozapine augmentation strategy were included. These studies are summarized in online Supplementary Information Supplementary Data.

Citalopram.

One RCT59 showed significantly superior efficacy of citalopram to placebo on total symptom severity. No significant departure was institute between citalopram and placebo for positive PANSS subscores. Nonetheless, citalopram was establish to be superior to placebo regarding negative symptoms.

Fluoxetine.

The RCT24 examining the efficacy of fluoxetine did non study PANSS total score. No significant differences were found between fluoxetine and placebo for positive symptom severity nor for negative symptoms.

Mirtazapine.

A high mean weighted effect size was obtained regarding total symptom severity for mirtazapine; yet, significance was non reached (figure 4). There was very high heterogeneity among these studies for total symptom score besides as for negative symptoms. On both measures, Zoccali et al60 showed large effect sizes, while Berk et al61 did not. Detailed inspection of the methods practical in the two RCTs could not identify a reason for this extreme discrepancy.

Fig. 4.

Individual outcome sizes of mirtazapine augmentation for full symptom severity (positive and negative syndrome scale/brief psychiatric rating scale).

No significant difference was found between mirtazapine and placebo for PANSS-positive score nor for negative symptom score. Heterogeneity for the positive symptoms was low. Statistical findings of these meta-analyses are summarized in table 1.

Antipsychotics

We included 10 studies apropos the efficacy of antipsychotic drugs as clozapine augmentation strategy, summarized in online Supplementary Information, table 4.

Amisulpride.

Ane study62 on the efficacy of amisulpride in augmenting clozapine yielded no significant difference between amisulpride and placebo regarding total symptom severity. Amisulpride did non differ from placebo for positive symptoms nor for negative symptoms.

Aripiprazole.

The ii RCTs66,67 yielded no meaning deviation between aripiprazole and placebo for total symptom score (see effigy 5). The degree of heterogeneity was depression. In addition, no significant departure was found betwixt aripiprazole and placebo for both the PANSS-positive and -negative scores. Concerning positive symptoms, studies were homogeneous. However, the caste of heterogeneity for the negative symptoms was loftier.

Fig. five.

Issue of aripiprazole on symptom severity (total positive and negative syndrome calibration/brief psychiatric rating scale scores).

Haloperidol.

No pregnant difference was observed betwixt haloperidol and placebo regarding change in full symptom severity. In addition, haloperidol did non differ from placebo for positive nor for negative symptoms.

Risperidone.

The overall outcome size showed no meaning deviation between risperidone and placebo for total symptom score, with moderate to high heterogeneity, see figure 6. For positive symptoms, the meta-analysis showed no meaning difference betwixt risperidone and placebo. Heterogeneity among studies was high. The standardized mean difference regarding negative symptoms was not significant, with moderate heterogeneity among studies.

Fig. half-dozen.

Meta-analysis of risperidone augmentation for full symptom severity (positive and negative syndrome scale/brief psychiatric rating scale).

Sulpiride.

Sulpiride was superior to placebo in reducing total symptom severity. Regarding positive and negative symptoms, sulpiride was also superior to placebo. Statistical findings of these meta-analyses are summarized in table 1.

Glutamatergic Drugs

7 studies concerning the efficacy of glutamatergic drugs in augmenting clozapine were included, summarized in online Supplementary Information, table v.

CX516.

CX516 was superior to placebo on total symptom severity. Regarding positive symptom severity, no difference was plant betwixt CX516 and placebo. The effect on negative symptom severity was superior for CX516.

d-cycloserine.

Only the scores on the negative subscales were provided, which yielded no significant difference.

d-serine.

PANSS total scores were non provided. d-serine was not superior to placebo for positive symptoms nor for negative symptoms.

Glycine.

The standardized hateful departure for total symptom severity was non pregnant and studies were homogeneous (effigy seven). The standardized hateful difference for positive symptoms was not pregnant, with a loftier degree of heterogeneity. For negative symptom severity, the standardized mean departure was not significant, with low heterogeneity.

Fig. 7.

Individual effect sizes of glycine augmentation for total symptom score (positive and negative syndrome calibration/brief psychiatric rating calibration).

Sarcosine.

No meaning difference was observed between sarcosine and placebo regarding change in total symptom severity. Apropos positive symptoms, sarcosine did not differ from placebo, nor for negative symptoms. Statistical findings of these meta-analyses are summarized in tabular array one.

Side Furnishings

Quantitative measures of side effects are listed in the online Supplementary Data, table half dozen. These data were too various to perform a meta-analysis. Qualitative inspection did not show consistently higher or lower side effects in the augmentation group.

Word

This study aimed to systematically review all available double-blind RCTs on pharmacological additions for clozapine-resistant patients with schizophrenia or schizoaffective disorder. We meta-analyzed 29 RCTs reporting on xv unlike augmentation strategies that included 1066 patients in total. Better improvement of total symptom severity than placebo was establish for lamotrigine, sulpiride, citalopram, and CX516 (a glutamatergic agonist). The superior efficacy of lamotrigine was only present if an outlier remained included in the meta-assay. For sulpiride, citalopram, and CX516 results were retrieved from single RCTs. Significant better efficacy on positive symptom severity was found for topiramate and sulpiride. After outlier removal the significant effect for topiramate disappeared. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Regarding clozapine augmentation with mood stabilizers, the significant effect size for lamotrigine was based on one study that deviated strongly from the others. The remaining four RCTs consistently showed no superior efficacy of lamotrigine than placebo. In a similar vein, the significant outcome of topiramate on positive symptom severity depended on a single study with a strongly diffusive finding. Later exclusion of that written report, topiramate was no longer superior to placebo. Thus, for both lamotrigine and topiramate, there is currently not enough bear witness to regard these components as constructive augmentation strategies for patients with bereft response to clozapine. It is uncertain if this finding can be extrapolated to other mood stabilizing drugs. Pocket-sized et al26 compared addition of lithium with placebo in a double-blind study and observed improvement with lithium only for schizoaffective patients but not for patients with schizophrenia.

Augmentation with antidepressants did not better total symptom severity, except for citalopram. While citalopram caused a larger decrease in negative symptom severity than placebo, this effect was not nowadays for fluoxetine or mirtazapine. None of the three antidepressants showed a greater improvement of positive symptoms than placebo. The addition of a 2nd antipsychotic drug to clozapine yielded negative results, with one exception. Aripiprazole was not amend than placebo in decreasing full, positive, or negative symptoms nor was risperidone. Effects of amisulpride on all measurements were comparable to placebo, while sulpiride, a substance of pharmacological similarity, showed ameliorate improvement than placebo on total symptom severity and both positive and negative subscores. A possible explanation for this difference could be the short duration of the amisulpride trial. Some other RCT on amisulpride augmentation, which did not meet inclusion criteria for this study, measured furnishings of 6 treatment weeks but likewise plant no comeback in total symptom severity74. Wang et al75 reviewed 3 trials adding sulpiride to clozapine, finding a subtle do good of sulpiride over placebo. Two of the included studies were open label, and therefore non included in the current study. These open-label studies did not replicate the efficacy of sulpiride reported by Shiloh et al.23 Clearly, the positive effect of sulpiride on total, positive, and negative symptom severity needs replication before augmentation with this drug should be recommended.

When the effects of glutamatergic drugs are summarized, the full general picture shows similar effects than placebo on total symptom severity and on positive and negative subscores; CX516 existence the but positive exception, with superior improvement on total symptom severity and negative symptom severity. However, as glutamatergic drugs are experimental, CX516 may not be a start choice in clinical practice.

Several other authors have reviewed augmentation strategies for clozapine, the majority of them concentrated on adding a second antipsychotic drug. Taylor and Smith76 meta-analyzed augmentation of clozapine with any second antipsychotic agents. They included 10 RCTs that showed marginally superior consequence compared with placebo for total symptom severity. Barbui et al77 reviewed antipsychotic addition to clozapine, which also included open-characterization studies. Coinciding to our results, they institute only pocket-size or absent-minded efficacy of augmentation. Kontaxakis et al78 qualitatively reviewed all studies on risperidone addition to clozapine. Their results suggested that risperidone augmentation is an effective strategy for clozapine-resistant patients. However, their positive conclusion may result from the inclusion of instance reports and open up case series. Tiihonen79 quantitatively summarized the effect of lamotrigine add-on, including the same studies as in this review. As they did not identify Zoccali et al56 every bit an outlier, they arrived to a slightly more positive conclusion.

Limitations

The major limitation of this study is the relative small numbers of RCTs that could be included per drug. For some pharmacological substances, we could include single studies. This makes our database not robust against both type I and type Two errors. The magnitude of the effect sizes of therapeutic interventions in mental health can change considerably with the accumulation of new data,80 and some pharmacological augmentations may yield significant effect sizes on the advent of new RCTs, while other (possibly sulpiride) may decrease in consequence size when more studies become available. A possibility to subtract the run a risk for type 2 errors would accept been to pool studies on drugs with similar pharmacological mechanisms, such as SSRIs or amino acids that stimulate the Northward-methyl D-aspartate receptors. In this article, we decided to nowadays results on unmarried drugs, as findings from pooled meta-analyses are difficult to translate into clinical practice. In improver, many vaguely acquainted agents, such as topiramate and lamotrigine, differ to such a large extent in their mechanism of action that pooling would not atomic number 82 to meaningful results.

In conclusion, the general movie emerges that at that place is currently no replicated evidence for any pharmacological augmentation strategy to combat resistant total, positive, or negative symptoms in clozapine-treated patients. All positive effects were either based on one outlying report or derived from a single RCT.

Funding

De Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)/ZonMW (Dutch Scientific Inquiry Organisation) Clinical Fellowship 2009 (4000703-97-270) and NWO/ZonMW (Dutch Scientific Research Organization) Innovation Impulse (Vidi) 2009 (017.106.301) to Dr Sommer.

The authors would like to thank Dr Zhida Xu for extracting the correct information from the Chinese publications. In addition, we would like to thank the contacted authors for their time and free energy to provide additional data to enable this meta-analysis. The authors Iris Sommer, Marieke Begemann, and Anke Temmerman have no conflicts of involvement relating to this commodity. Stefan Leucht received speaker/consultancy/advisory board honoraria from SanofiAventis, Bristol-Myers-Squibb, Actelion, EliLilly, Essex Pharma, AstraZeneca, GlaxoSmithKline, Janssen/Johnson and Johnson, Lundbeck and Pfizer. SanofiAventis and EliLilly supported research projects past Stefan Leucht.

Supplementary Material

Supplementary Data is bachelor at http://schizophreniabulletin.oxfordjournals.org.

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Source: https://academic.oup.com/schizophreniabulletin/article/38/5/1003/1897952

Non-glutamatergic Clozapine Augmentation Strategies a Review and Meta-analysis

Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

Abstract

Introduction

Methods

Literature Search

Inclusion

Outcome Measures

Statistical Analyses

Results

Antiepileptic Medication

Lamotrigine.

Topiramate.

Antidepressants

Citalopram.

Fluoxetine.

Mirtazapine.

Antipsychotics

Amisulpride.

Aripiprazole.

Haloperidol.

Risperidone.

Sulpiride.

Glutamatergic Drugs

CX516.

d-cycloserine.

d-serine.

Glycine.

Sarcosine.

Side Furnishings

Word

Limitations

Funding

Supplementary Material

References

Supplementary data

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