or treatment-resistant schizophrenia patients treated with clozapine.

Review

1.

Introduction

2.

Augmentation with other APs

3.

Augmentation with

Maria Rosaria A Muscatello†, Antonio Bruno, Pasquale De Fazio, Cristina Segura-Garcia, Gianluca Pandolfo & Rocco Zoccali

antidepressants

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/07/14 For personal use only.

Augmentation strategies in partial responder and/or treatmentresistant schizophrenia patients treated with clozapine

4.

Augmentation with mood stabilizers

5.

Augmentation with other agents

6.

Augmentation with electroconvulsive therapy

7.

Conclusion

8.

Expert opinion

†

University of Messina, Department of Neurosciences, Messina, Italy

Introduction: Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals. Areas covered: This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were ‘clozapine augmentation’, ‘clozapine and add-on’ and ‘treatment-resistant schizophrenia’, with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents. Expert opinion: Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well-designed trials are required to establish true efficacy and safety of CLZ augmentation strategies. Keywords: add-on, clozapine augmentation, refractory, treatment-resistant schizophrenia Expert Opin. Pharmacother. (2014) 15(16):2329-2345

1.

Introduction

Schizophrenia is a severe and disabling mental illness characterized by a set of signs and symptoms, which include thought and perceptive distortions, such as delusions and hallucinations, disorganized speech and behavior, alogia, affective flattening, social withdrawal, often associated with other symptom dimensions, such as cognitive impairment and affective features. Although the chronic and relapsing course and the outcome of schizophrenia have been substantially modified by the introduction of antipsychotic (AP) drugs, it is approximately estimated that around 20 -- 30% of all schizophrenia patients are treatment-resistant [1]. Treatment resistance was defined, according Kane’s criteria [2], as follows: i) evidence of adequate previous medication trials (at least 3-week to 6-week trials in the preceding 5 years with first-generation APs (FGAs) from two chemical classes at doses equivalent to 1000 mg/day of chlorpromazine without significant clinical improvement; ii) persistent positive symptoms, with scores of moderate or worse on at least two of four positive symptom items on the Brief Psychiatric Rating Scale (BPRS); iii) illness severity documented by a score of ‡ 45 on the 18-item (BPRS, scored 1 -- 7) [3], as well as a severity score of ‡ 4 on ‡ 2 10.1517/14656566.2014.956082 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

2329

M. R. A. Muscatello et al.

Article highlights. .

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.

.

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The concept of treatment-resistant schizophrenia, nonor partial responders, optimizing clozapine (CLZ) treatment and polypharmacy when CLZ is partially effective on clinical symptoms of schizophrenia is reviewed. Update on recent research and literature regarding CLZ augmentation strategies for treatment-resistant schizophrenia is given. Most add-on treatments are not supported by evidence-based scientific criteria. Main classes of drugs as CLZ add-on treatment in refractory populations: antipsychotics, antidepressants, anticonvulsants and other agents are discussed. The restriction of CLZ use, as well as the quite diffused attitude of psychiatrists to consider CLZ as the last resort in the treatment of schizophrenia, are factors that presumably hamper the efficacy of CLZ treatment, thus increasing the proportion of patients who are nonresponsive to CLZ treatment. The treatment of refractory, highly symptomatic patients still remains a challenge, and it represents a persistent public health burden accounting for the majority of the total health cost of treating schizophrenia. In these cases, any treatment that potentially could improve the quality of life of treatment-refractory patients should be considered. Although some augmentation strategies seem to be encouraging and relatively safe, there is still a lack of large, randomized controlled trials providing strong evidence-based support for CLZ-resistant patients. More research is needed to further investigate this topic.

This box summarizes key points contained in the article.

BPRS psychotic items (i.e., conceptual disorganization, suspiciousness, hallucinatory behavior and unusual thought content), and by a score of at least moderate on the Clinical Global Impression scale; and iv) no period of good social or occupational functioning in the preceding 5 years. Nevertheless, a comprehensive definition of treatment-resistant schizophrenia partially lacks of agreement; the main critic is that Kane’s criteria rely mostly on positive symptoms improvement, whereas other symptom dimensions, such as negative and cognitive symptoms, seem to have a significant impact on community outcome, well-being and independent living [4,5], and they need separate interventions, both pharmacological and psychosocial [6]. The second-generation AP drug (SGA) clozapine (CLZ), a dibenzazepine structurally derived from loxapine, is the best evidence-based therapeutic option for treatment-resistant schizophrenia patients [7]. It has been estimated that the response rate to CLZ is about 50%, irrespective of partial response or nonresponse to prior treatment with other APs [8]; further, CLZ showed anti-suicidal and anti-aggressive properties [9,10]. Although it has been shown that up to 70% of treatment-resistant schizophrenia patients are also resistant to CLZ [11], it should be kept in mind that variables such as poor compliance, the presence of comorbidities and side effects 2330

are involved in clinical response and they should be carefully considered as possible causes of pseudoresistance [12]. First, adherence to the prescribed medication cannot be taken as proven, and Clinical Drug Monitoring (CDM) remains the more reliable way of distinguishing true resistance from pseudoresistance. Plasma level thresholds of 1050 -- 1260 nmol/l for CLZ have been associated with treatment response, although some patients may respond at lower levels, whereas levels higher than 2100 nmol/l may increase the risk of side effects, contributing to poor adherence and early dropouts, and intoxication is generally seen at levels over 2700 nmol/l [13]. The adequate duration of CLZ treatment needed to achieve clinical response is another matter of debate, since in some authors’ opinion CLZ treatment usually show clinical efficacy within 6 months [14]. Conversely, a subpopulation of late responding schizophrenia patients showing delayed responses, occurring after to 1 year of treatment have been identified [15]. According to this latter observation, it has been suggested that the duration of trials aimed to evaluate CLZ response should be significantly longer than the usual 4 -- 8 weeks period, which is routinely employed with other APs [16]. Therefore, when a trial with CLZ, adequate for dose and duration, fails to lead to symptoms improvement, augmentation of CLZ with a second AP is common in clinical practice [17], although insufficient support for the safety and efficacy of combining CLZ with an additional AP was found [18]. Further augmentation strategies have involved other classes of drugs, such as antidepressants, mood stabilizers and other agents; nevertheless, most studies are case reports and case series, retrospective chart reviews and small sampled uncontrolled trials [19]. Within this context, although CLZ remains the only AP convincingly shown to be more effective than others in controlling psychotic symptoms [20], the treatment of schizophrenia is still marked by unmet needs. Several reviews and expert opinions on CLZ augmentation and treatment-resistant schizophrenia have been published [17,19,21-25]. The aim of the present review was to update available data on clinical efficacy, tolerability and safety of pharmacological augmentation of CLZ in partial or nonresponding schizophrenia patients. The following scientific databases were consulted to find all the studies published in English from 1990 to 2014: Medline (OvidSP), CINAHL (Ebsco), EMBASE (Ovid), PsychINFO (EBsco), AgeLine, Cochrane Database of Systematic Reviews, Database of Abstract of Reviews Effects; additional references were identified from the bibliographies of published articles. Keywords included were: ‘clozapine augmentation’, ‘adjunctive to clozapine’, ‘clozapine and add-on’, ‘adjunct to clozapine’, ‘combination clozapine’, ‘clozapine combined’ ‘clozapine responders’, ‘clozapine non-responders’, ‘resistant/refractory schizophrenia’, ‘ultra-resistant schizophrenia’, ‘super refractory schizophrenia’, ‘clozapine-resistant’, ‘clozapine antipsychotics’, ‘clozapine antidepressants’, ‘clozapine mood stabilizers’, ‘electroconvulsive therapy augmentation’ and ‘clozapine and electroconvulsive’. We selected articles for

Expert Opin. Pharmacother. (2014) 15(16)

Augmentation strategies in partial responder and/or treatment resistant schizophrenia patients treated with clozapine

review if their content was informative of the topic; searches were last updated on 10 June 2014.


2.

Augmentation with other APs

The association between CLZ and other APs is fairly common both in clinical practice and in experimental trials; nevertheless, the true efficacy of this augmentation strategy still remains questioned [17]. The following APs have been associated with CLZ: risperidone [26-32], aripiprazole [33-38], sulpiride [39], amisulpride [40-45], ziprasidone [46-48], pimozide [49,50] and sertindole (Table 1) [51]. Further data on CLZ augmentation with olanzapine [52,53], asenapine [54], pipamperone [55] and paliperidone [56] were reported in case reports. The combination of CLZ with risperidone has been the most tested in partial or nonresponder patients with schizophrenia, although mixed results have emerged from randomized controlled trials (RCTs) regarding the efficacy of this strategy. A 6-week, double-blind study showed that adjunctive risperidone treatment was not more effective than placebo on psychopathology and quality of life in schizophrenia patients partially responsive to CLZ [26]. Contrarily, a 12-week RCT on 40 therapy-resistant patients with schizophrenia showed that risperidone up to 6 mg/day added to CLZ was effective in improving positive and negative symptoms, as documented by the BPRS and Scale for the Assessment of Negative Symptoms (SANS) score changes [27]. Further results demonstrated only a modest efficacy of adjunctive risperidone [31] or no efficacy versus placebo [28,30] on clinical symptoms. Although risperidone has been the most-investigated CLZ augmentation treatment, the results reported by the reviewed trials are almost conflicting, with open trials providing more positive outcomes than RCTs. Beyond overall small sample sizes, the observed discrepancies are probably due to differences in study designs and methods, such as drug dosage, treatment duration, inclusion of refractory or partial-responder patients; thus, the comparability of such studies remains low, and it is difficult to assess the true efficacy of this strategy adequately. Concerning tolerability and safety, risperidone add-on was associated with unfavorable cognitive effects, such as worsened measures of verbal working memory, verbal learning and memory and attention [29], increase in prolactin levels and fasting blood glucose and marked sedation [26,28,30,31]. The augmentation of risperidone does not essentially change the outcome of patients with schizophrenia treated with CLZ. This has been confirmed by a recent meta-analysis examining only five studies on risperidone add-on based on the inclusion criteria of response rates and good quality according to the Newcastle--Ottawa Scale [25]. Conflicting data on the efficacy of aripiprazole augmentation of CLZ have been reported. Aripiprazole add-on to CLZ did not offer statistically significant advantage over placebo treatment for total symptom severity, although it was superior to placebo in improving negative [33], positive symptoms and overall clinical state, whereas no significant

effect on cognitive symptoms was observed [37]. Concerning metabolic effects, the combination of aripiprazole plus CLZ resulted in significant reduction in body weight, body mass index, fasting cholesterol and triglycerides levels [35]. Regarding pharmacokinetic interactions, aripiprazole did not appear to modify CLZ serum levels, as documented by CDM [34,36]. In the long-term treatment (12 months), aripiprazole offered no substantial benefit over haloperidol in efficacy, although it was better tolerated in term of side effects [38]. One pioneer study on sulpiride augmentation of CLZ showed that sulpiride was more effective than placebo in improving positive and negative symptoms in partial responder patients with schizophrenia [39]. Augmentation of CLZ with amisulpride in treatment-resistant schizophrenia has been evaluated in open-label trials [40-42] that reported a significant reduction of primary and secondary outcome measures. A significant improvement of residual depressive symptoms, global functioning and quality of life, but not positive and negative symptoms, was shown in a randomized, double-blind, placebo-controlled trial on a small sample of partial responder schizophrenia patients treated with CLZ [44]; however, high rates of adverse effects, such as increase in prolactin serum levels, tremor, akathisia and bradykinesia were documented. A randomized, singleblind, head-to-head comparison of amisulpride and quetiapine in schizophrenia patients who were partially responsive to CLZ monotherapy showed that the combination amisulpride and CLZ was more effective than quetiapine and CLZ in treating both positive and negative symptoms [43]. Recently, a pilot study [45] on six schizophrenia patients treated with CLZ and demonstrating aggressive and violent behaviors showed that amisulpride add-on was associated with a significant reduction of aggression and violence; the incidence of adverse events was negligible. Ziprasidone has been compared with risperidone as augmentation strategies in a RCT [46] and in a long-term study [47]. Both drugs showed similar efficacy on clinical symptoms, but different side-effect profiles; risperidone treatment was associated with extrapyramidal symptoms, more weight gain and hyperprolactinemia, whereas ziprasidone caused more QTc prolongation than risperidone. An open-label trial aimed to evaluate the effect of ziprasidone 160 mg/day in schizophrenia or schizoaffective patients with olanzapine or CLZ-associated medical morbidity (metabolic syndrome) showed that ziprasidone did not produce significant improvement neither in metabolic parameters and weight nor in clinical symptoms in the study sample [57]. A recent double-blind, placebo-controlled trial of ziprasidone augmentation of CLZ in a sample of treatment-resistant schizophrenia patients showed that ziprasidone was more effective than placebo in reducing negative and general psychopathological symptoms and in improving cognitive measures; coadministration with ziprasidone was associated with no changes in plasma CLZ and desmethylclozapine and no significant QTc prolongation was observed [48]. The addition of pimozide to CLZ was not effective on positive, negative or general symptoms as measured by Positive


2331



Table 1. Main studies on CLZ augmentation with antipsychotics. Authors/year of publication

Augmentation agent (mg/day)

Active comparator/ placebo

Trial duration (weeks)

Number of patients

Principal outcome measures

Main efficacy results

Anil Yag˘ciog˘lu et al. (2005) [26]

RIS (up to 6 mg)

PLA

6

30 16 RIS 14 PLA

PANSS

PANSS-P: RIS less effective than PLA

Josiassen et al. (2005) [27]

RIS (up to 6 mg)

PLA

12

40 20 RIS 20 PLA

BPRS SANS

BPRS, SANS: RIS more effective than PLA at weeks 6 and 12

Honer et al. (2006) [28]

RIS (3 mg)

PLA

8

68 34 RIS 34 PLA

PANSS

No statistical differences between RIS and PLA

Freudenreich et al. (2007) [30]

RIS (4 mg)

PLA

6

24 11 RIS 13 PLA

PANSS

Nonsignificant decrease in PANSS total score

Wiener et al. (2010) [31]

RIS (4 mg)

PLA

16

65 30 RIS 30 PLA

BPRS SANS

No statistical differences between RIS and PLA in ITT analyses

Kuwilsky et al. (2010) [32]

RIS (up to 4 mg)

ZIP

26 -- 52

24 12 RIS; (4 compl) 12 ZIP (7 compl)

PANSS SANS

Significant improvements at weeks 26 and 52

Chang et al. (2008) [33]

ARI (up to 30 mg)

PLA

8

61 29 ARI 32 PLA

BPRS

No significant differences between ARI and PLA in BPRS total score

Fleischacker et al. (2010) [35]

ARI (range 5 -- 15 mg)

PLA

16

207

PANSS

No statistical differences between ARI and PLA

Benedetti et al. (2010) [36]

ARI (range 5 -- 15 mg)

NA

2

7

BPRS

Significant decrease in BPRS total score

Muscatello et al. (2011) [37]

ARI (up to 15 mg)

PLA

24

31

BPRS SANS SAPS

Significant SAPS total score reduction; on SANS only ‘alogia’ scale score reduction

Cipriani et al. (2013) [38]

ARI (mean dose 11.8 ± 5.1 mg)

Haloperidol (mean dose 2.8 ± 1.7 mg/day)

12 months

106

BPRS

No statistical differences between ARI and haloperidol

Shiloh et al. (1997) [39]

SUL (up to 600 mg)

PLA

10

28 16 SUL 12 PLA

BPRS SAPS SANS

Significant improvements in positive and negative psychotic symptoms

Agelink et al. (2004) [40]

AMI (up to 800 mg)

NA

9.7 months (mean)

7

BPRS

Statistically significant improvement of the mean BPRS score

Munro et al. (2004) [42]

AMI (up to 800 mg)

NA

24

28

PANSS SANS

Statistically significant improvement of the mean PANSS and SANS scores

AMI: Amisulpride; ARI: Aripiprazole; BPRS: Brief psychiatric rating scale; CGI: Clinical global impression scale; CLZ: Clozapine; compl: Completers; ITT: Intention to treat; NA: Not available; PANSS-T (P, N, GP): Positive and negative syndrome scale-total (positive, negative and general psychopathology subscales); PIM: Pimozide; PLA: Placebo; QUE: Quetiapine; RIS: Risperidone; SANS: Scale for the assessment of negative symptoms; SAPS: Scale for the assessment of positive symptoms; SER: Sertindole; SUL: Sulpiride; ZIP: Ziprasidone.

2332




Table 1. Main studies on CLZ augmentation with antipsychotics (continued). Authors/year of publication




Number of patients



Kampf et al. (2005) [41]

AMI (not specified)

NA

20

14

CGI

Significant decrease of the mean CGI score

Genç et al. (2007) [43]

AMI (up to 600 mg)

QUE (up to 900 mg/day)

8

50 27 AMI 23 QUE

BPRS SAPS SANS

AMI more effective than QUE

Assion et al. (2008) [44]

AMI (400 -- 600 mg)

PLA

6

16 7 AMI (400 mg/day) 6 AMI (600 mg/day) 3 PLA

BPRS

No reduction in BPRS total score was achieved

Zink et al. (2009) [46]

ZIP (134 ± 34.4 mg)

RIS (3.82 ± 1.8 mg/day)

6

24 12 ZIP 12 RIS

PANSS

Both groups showed significant reductions of positive and negative symptoms


ZIP (80 mg)

PLA

16

40 20 ZIP 20 PLA

PANSS

PANSS-N/GP: ZIP more effective than PLA

Friedman et al. (2011) [49]

PIM (up to 8 mg)

PLA

12

53 25 PIM 23 PLA

PANSS

No statistical differences between PIM and PLA

GunduzBruce et al. (2013) [50]

PIM (up to 4 mg)

PLA

12

28 14 PIM 14 PLA

BPRS SANS

No significant effect on positive and negative symptoms

Nielsen et al. (2012) [51]

SER (16 mg)

PLA

12

50 25 SER 25 PLA

PANSS CGI

Augmentation was not superior to PLA

AMI: Amisulpride; ARI: Aripiprazole; BPRS: Brief psychiatric rating scale; CGI: Clinical global impression scale; CLZ: Clozapine; compl: Completers; ITT: Intention to treat; NA: Not available; PANSS-T (P, N, GP): Positive and negative syndrome scale-total (positive, negative and general psychopathology subscales); PIM: Pimozide; PLA: Placebo; QUE: Quetiapine; RIS: Risperidone; SANS: Scale for the assessment of negative symptoms; SAPS: Scale for the assessment of positive symptoms; SER: Sertindole; SUL: Sulpiride; ZIP: Ziprasidone.

and Negative Syndrome Scale (PANSS) in patients with schizophrenia and schizoaffective disorder showing a partial response to CLZ monotherapy [49]. Such results have been confirmed by a randomized, placebo-controlled trial which showed that pimozide plus CLZ was not an effective strategy for improving positive and negative symptoms and neurocognitive functions [50]. Sertindole, a non-sedating AP drug currently available for the treatment of schizophrenia in many countries under special safety conditions [58], has been evaluated as augmentation treatment in a 12-week, double-blind, placebo-controlled study in a sample of CLZ partial-responder schizophrenia patients. Results have shown that sertindole was not superior to placebo in improving clinical symptoms or cognitive functioning and motor speed, whereas in some patients psychotic symptoms worsened and QTc interval increased [51]. Case studies suggested the efficacy of olanzapine add-on to CLZ on clinical symptoms [52,53]; however, this

combination was associated with a significant risk of metabolic syndrome [59]. Asenapine was effective on catatonic symptoms, dysphoric mood, sleep disorders, impulsivity, psychomotor agitation and speech, but showed no benefit on dysphoric mood and psychomotor agitation in a bipolar patient with catatonic and psychotic symptoms who was treated with CLZ [54]. Pipamperone and sodium valproate augmentation of CLZ was effective on positive (auditory hallucinations, delusions), negative (anhedonia and social withdrawal) and disorganization (formal thought disorder) symptoms in a 37-year-old patient with refractory schizophrenia. The combination was well tolerated: neither extrapyramidal nor myelosuppressive adverse effects were observed [55]. Paliperidone 9 mg/day was effective in treating persistent psychotic and depressive symptoms and social functioning in a woman affected by schizoaffective disorder, depressed type, who was treated with CLZ up to 200 mg/day [56].


2333



Table 2. Augmentation with antidepressants. Authors/year of publication




Number of patients



Buchanan et al. (1996) [61]

FLU (up to 80 mg)

PLA

8

33 18 FLU 15 PLA

BPRS

No significant differences between FLU and PLA

Spina et al. (1998) [62]

FLU (20 mg)

NA

8

10

SANS SAPS


Anghelescu et al. (1998) [63]

Paroxetine (20 mg)

NA

6

14

PANSS

PANSS-T/N: score reduction

Lu et al. (2000) [64]

Fluvoxamine (50 mg)

NA

4

18

CGI

Significant decrease of the mean CGI score

Lan et al. (2006) [66]

Citalopram (not specified)

PLA

61

PANSS

PANSS-T/N: Citalopram more effective than PLA

Zoccali et al. (2004) [67]

MIR (30 mg)

PLA

8

24 12 MIR 12 PLA

BPRS SANS SAPS

BPRS, SANS: MIR more effective than PLA

Delle Chiaie et al. (2007) [68]

MIR (30 mg)

NA

8

15

BPRS SANS


Mico` et al. (2011) [69]

Duloxetine (60 mg)

PLA

16

33 17 DUL 16 PLA

PANSS

PANSS-N/GP: Duloxetine more effective than PLA

Bruno et al. (2014) [71]

Agomelatine (up to 50 mg)

NA

16

20

PANSS

At a dosage of 50 mg/day significant score reduction in all PANSS domains

BPRS: Brief psychiatric rating scale; CGI: Clinical global impression scale; FLU: Fluoxetine; MIR: Mirtazapine; NA: Not available; PANSS-T (P, N, GP): Positive and Negative Syndrome Scale-Total (positive, negative and general psychopathology subscales); PLA: Placebo; SANS: Scale for the assessment of negative symptoms; SAPS: Scale for the assessment of positive symptoms.

It must be clearly stated that these case reports, although recent and interesting, do not allow drawing any conclusion, and the abovementioned augmentation strategies need further investigation. 3.

Augmentation with antidepressants

Antidepressant drugs are commonly used as an augmentation strategy to enhance CLZ efficacy based on the therapeutic rationale of addressing negative and resistant symptoms [60]. Since tricyclic antidepressants added to CLZ showed little benefit and an increased risk of toxicity [21], the evidence from literature is more in favor of augmentation with selective serotonin-reuptake inhibitors and more recent compounds. Main studies on antidepressants augmentation of CLZ are reported in Table 2. Fluoxetine augmentation was not more effective than placebo on residual positive, negative, depressive and obsessivecompulsive symptoms in partial responder schizophrenia patients [61]. In addition, it has been pointed out that 2334

fluoxetine augmentation increased plasma concentration of CLZ and its metabolites, although a careful monitoring is needed in order to avoid serious side effects [62]. Paroxetine augmentation was effective in reducing negative symptoms and was well tolerated in an open, 6-week trial on a small sample of CLZ-treated schizophrenia or schizoaffective patients with prominent negative symptoms; the findings are limited by the open design and by the sample size [63]. Better results on overall clinical symptoms were seen with fluvoxamine add-on in CLZ-resistant schizophrenia patients [64]; however, since fluvoxamine is a potent CYP1A2 inhibitor, it decreases CLZ metabolism. The increase of CLZ plasma levels might partially explain the positive effects reported with fluvoxamine augmentation; moreover, the risk of side effects also proportionally increases. Fluvoxamine added to CLZ has also been shown to decrease plasma levels of norclozapine, a toxic metabolite of CLZ, which is mainly associated with side effects, such as weight gain and metabolic syndrome in CLZ-treated patients [65].




Table 3. Augmentation with mood stabilizers. Authors/year of publication



Kelly et al. (2006) [74]

DVX (750 -- 2000 mg)

LIT (900 -1800 mg)

Dursun and Deakin (2001) [75]

LMT (100 -- 300 mg)

Tiihonen et al. (2003) [78]


Number of patients



Retrospective

49 9 LIT 15 DVX 25 NC

BPRS

DVX and LIT more effective than clozapine monotherapy at month 1

TOP (225 -300 mg)

24

26 17 LMT 9 TOP

BPRS

LMT more effective than TOP

LMT (up to 200 mg)

PLA

14

34 16 LMT 18 PLA

PANSS

PANSS-P/GP: LMT more effective than PLA

Kremer et al. (2004) [76]

LMT (up to 400 mg)

PLA

10

38 25 LMT 13 PLA

PANSS

No significant differences between LMT and PLA

Goff et al. (2007) [77]

LMT (100 -- 400 mg)

PLA

12

21 12 LMT 9 PLA

PANSS

No significant differences between LMT and PLA

Zoccali et al. (2007) [79]

LMT (up to 200 mg)

PLA

24

51 26 LMT 25 PLA

BPRS SANS SAPS

LMT more effective than PLA

Vayısog˘lu et al. (2013) [80]

LMT (up to 200 mg)

PLA

12

34 17 LMT 17 PLA

PANSS

PANSS-T/N: PLA more effective than LMT

Tiihonen, (2005) [82]

TOP (300 mg)

PLA

12

26 13 TOP 13 PLA

PANSS

PANSS-GP: TOP more effective than PLA

Afshar et al. (2008) [83]

TOP (up to 300 mg)

PLA

8

32 16 TOP 16 PLA

PANSS

Clinical response was significantly higher in TOP group than PLA


TOP (up to 200 mg)

PLA

24

43 19 TOP 24 PLA

BPRS SANS SAPS

No significant differences between TOP and PLA

Behdani et al. (2011) [84]

TOP (200 -- 300 mg)

PLA

17

80 40 TOP 40 PLA

PANSS

No significant differences in PANSS scores between TOP and PLA

BPRS: Brief Psychiatric Rating Scale; DVX: Divalproex; LIT: Lithium; LMT: Lamotrigine; NC: No comparator; PANSS-T (P, N, GP): Positive and Negative Syndrome Scale-Total (Positive, Negative and General Psychopathology subscales); PLA: Placebo; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms; TOP: Topiramate.

One RCT showed significantly superior efficacy of citalopram over placebo on overall symptom severity and negative symptoms, whereas no significant differences were found between citalopram and placebo for positive symptoms [66]. Adjunctive treatment with mirtazapine was found to be effective in CLZ-treated schizophrenia patients with prominent negative symptoms [67]; moreover, mirtazapine add-on has been associated with improvement in cognitive performances [68]. In both studies, mirtazapine was well tolerated, and no relevant adverse events were reported, except for a modest weight increase.

A double-blind, placebo-controlled trial showed that adjunctive duloxetine to stable CLZ treatment had a beneficial effect on the negative and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients, whereas it did not have beneficial effect on executive cognitive functions [69]. Regarding pharmacokinetic interactions, it has been shown that concomitant duloxetine administration did not significantly change mean plasma concentrations of CLZ and norclozapine [70]. A recent open-label, uncontrolled trial has provided the first investigation of adjunctive agomelatine in a sample of


2335


Table 4. Augmentation with other agents.


Authors/year of publication

Augmentation agent



Number of patients



Potkin et al. (1999) [86]

GLY (30 g/day)

PLA

12

19 9 GLY 10 PLA

BPRS SANS

No significant treatment effects

Heresco-Levy et al. (1999) [88]

GLY (up to 90 g/day)

PLA

6

19 7 CLZ

BPRS PANSS

BPRS, PANSS-N: GLY more effective than PLA

Evins et al. (2000) [89]

GLY (60 g/day)

PLA

8

27 14 GLY 13 PLA

BPRS PANSS SANS

No significant treatment effect

Diaz et al. (2005) [87]

GLY (60 g/day)

PLA

28

12 6 GLY 6 PLA

PANSS

No significant treatment effect

Goff et al. (1996) [91]

D-CY

(5-15-50250 mg/day)

NA

8

10

SANS

Worsening of negative symptoms at 50 mg dose

Goff et al. (1999) [90]

D-CY

PLA

13

47 23 D-CY 24 PLA

PANSS SANS

D-CY

Tsai et al. (1999) [92]

D-SE

PLA

6

20 10 D-SE 10 PLA

PANSS

Nonsignificant decrease in PANSS score

Lane et al. (2006) [93]

SAR (2 g/day)

PLA

6

20 10 SAR 10 PLA

PANSS

No differences between the two groups

Goff et al. (2001) [94]

AMP (900 -- 2700 mg)

PLA

4

18 12 AMP 6 PLA

PANSS

AMP more effective than PLA

de Lucena et al. (2009) [95]

MEM (20 mg)

PLA

12

21 10 MEM 11 PLA

BPRS

Significant improvement was observed with MEM as compared with PLA

Stryjer et al. (2004) [96]

DON (up to 10 mg)

PLA

18

8 4 DON 4 PLA

PANSS

No significant difference between DON and PLA

Fenton et al. (2001) [97]

E-EPA (3 g/day)

PLA

16

75 37 E-EPA 38 PLA

PANSS

No differences were found between groups

Peet and Horrobin (2002) [98]

E-EPA (1-2-4 g/day)

PLA

12

31 9 E-EPA 1 g 9 E-EPA 2 g 6 E-EPA 4 g

PANSS

Statistically significant effect of E-EPA at the 2 g dose

Emsley et al. (2002) [99]

E-EPA (3 g/day)

PLA

12

18 9 E-EPA 9 PLA

PANSS

E-EPA group had significantly greater reduction of scores than PLA

(50 mg/day)

(30 mg/kg/day)

significantly worsened ratings of negative symptoms compared to PLA

AMP: Ampakine CX516; BPRS: Brief Psychiatric Rating Scale; CLZ: Clozapine; D-CY: D-cycloserine; DON: Donepezil; D-SE: D-serine; E-EPA: Ethyl-eicosapentaenoic acid; GLY: Glycine; MEM: Memantine; MIN: Minocycline; NA: Not available; PANSS-T (P, N, GP): Positive and Negative Syndrome Scale-Total (Positive, Negative and General Psychopathology subscales); PLA: Placebo; SANS: Scale for the Assessment of Negative Symptoms.

2336



Table 4. Augmentation with other agents (continued).


Authors/year of publication

Augmentation agent



Number of patients



Remington et al. (2012) [100]

Tetrabenazine (12.5 -- 75 mg/day)

PLA

12

41 30 CLZ

BPRS

No clinical improvement

Levkovitz et al. (2010) [101]

MIN (200 mg)

PLA

24

54 36 MIN 18 PLA

SANS PANSS

Significant improvement was observed with MIN as compared with PLA

AMP: Ampakine CX516; BPRS: Brief Psychiatric Rating Scale; CLZ: Clozapine; D-CY: D-cycloserine; DON: Donepezil; D-SE: D-serine; E-EPA: Ethyl-eicosapentaenoic acid; GLY: Glycine; MEM: Memantine; MIN: Minocycline; NA: Not available; PANSS-T (P, N, GP): Positive and Negative Syndrome Scale-Total (Positive, Negative and General Psychopathology subscales); PLA: Placebo; SANS: Scale for the Assessment of Negative Symptoms.

partial-responder schizophrenia patients [71]. Agomelatine augmentation was associated with improvement in clinical symptoms, overall psychopathological state and cognitive functioning; however, the small sample size, the lack of a control group, the open design and the non-blinded mode of rating do not allow for firm conclusions to be drawn. 4.

Augmentation with mood stabilizers

The augmentation of CLZ with lithium was evaluated on small samples of schizophrenia and schizoaffective patients, with better outcomes in the latter group. Concerning safety, although lithium appeared quite safe when administered at a dose within a moderate therapeutic range, and in the absence of other drugs that could interfere with CLZ metabolism, adverse events, mainly neurological abnormalities and granulocytosis, were reported [72,73]. Table 3 shows the main trials of CLZ augmentation with mood stabilizers. A single, retrospective, uncontrolled study has compared the efficacy of adjunctive divalproex sodium or lithium in treatment-resistant schizophrenia patients versus CLZ monotherapy. The addition of divalproex sodium was associated with general improvement of overall symptoms, particularly anxious and dysphoric symptoms; lithium also demonstrated efficacy on general symptoms, although its administration was associated with the increase in glucose blood levels [74]. Augmentation with lamotrigine has been rather studied. A naturalistic follow-up case series compared the efficacy of lamotrigine and topiramate, reporting positive effect only in the lamotrigine group [75]. Two studies have evaluated lamotrigine versus placebo add-on to ongoing AP therapy, both FGAs and SGAs [76], lamotrigine and SGAs [77], with conflicting results. However, in the abovementioned studies, the number of CLZ-treated patients was small, and the extent to which the study samples might be considered treatment-resistant is highly questionable. Two RCTs showed that lamotrigine augmentation with CLZ was superior compared to placebo on positive (mainly auditory hallucinations) and general psychopathological symptoms [78], and on positive, negative,

affective and general symptoms during 24-week treatment [79]. Conversely, a 12-week, double-blind, placebo-controlled trial did not show any benefit of augmentation of CLZ with lamotrigine in schizophrenia patients with partial response [80]. Regarding safety, this strategy was well tolerated; further, it has been demonstrated that lamotrigine at recommended doses (up to 200 mg/day) did not alter the steady-state plasma concentrations of CLZ, risperidone and olanzapine and their active metabolites [81]. Conflicting results are also evident regarding topiramate augmentation; data from RCTs showed a significant effect of topiramate on general psychopathological symptoms [82] and on positive, negative and overall symptoms in 8 weeks [83]. More recently, negative results emerged from a 24-week, double-blind, placebo-controlled study [58], and from a 17-week, placebo-controlled trial of adjunctive topiramate in schizophrenia patients who have had an incomplete clinical response to CLZ [84]. A recent critical review about the efficacy and safety of topiramate in treatment-refractory schizophrenia has shown that topiramate was associated with small or moderate benefits on clinical symptoms, although it may improve metabolic parameters and reduce AP-induced weight gain [85]. 5.

Augmentation with other agents

Further augmentation strategies have involved glutamatergic agents (glycine, D-cycloserine, D-serine, ampakine and memantine), acetylcholinesterase inhibitors, ethyl-eicosapentaenoic acid (E-EPA), tetrabenazine and minocycline (Table 4). Concerning glutamatergic agents in augmenting CLZ, the majority of research studied the efficacy of three agonists at the glycine site on the NMDA receptor: glycine, D-cycloserine and D-serine. Four double-blind, placebo-controlled trials have evaluated glycine add-on to CLZ alone [86,87] or to ongoing AP therapy, including CLZ [88,89]. Results about effectiveness of adjunctive glycine on positive and negative symptoms were conflicting, although generally negative. It must be pointed out that, in the abovementioned studies, the number of CLZ-treated patients was small; it has also been suggested that glycine is more effective when combined with FGAs


2337



than with CLZ [87,89]. Similarly, a dose-finding trial of adjunctive D-cycloserine in CLZ-treated schizophrenia patients showed that negative symptoms significantly worsened during D-cycloserine treatment at the dose of 50 mg/day, thus not confirming previous positive results obtained when D-cycloserine was combined with FGAs [90,91]. Regarding Dserine, one study confirmed that patients treated with CLZ did not improve in schizophrenic symptoms with D-serine treatment [92], and adjunctive treatment of sarcosine had no effects on clinical symptoms of schizophrenia patients who were receiving CLZ therapy [93]. A 4-week, placebo-controlled, preliminary study on a small sample of schizophrenia patients reported the improvement on total symptom severity with the addition of the glutamatergic agonist ampakine CX516 [94]. In a double-blind, randomized, placebo-controlled trial, the NMDA antagonist memantine add-on to CLZ was associated with a significant improvement of both positive and negative symptoms; however, results need to be interpreted with caution due to the small sample size [95]. The acetylcholinesterase inhibitor donepezil added to CLZ monotherapy did not demonstrated superiority over placebo on clinical symptoms in a double-blind, crossover study on a small sample of schizophrenia patients [96]. Studies on CLZ augmentation with E-EPA have reported conflicting results: a 16-week, double-blind trial found no evidence for efficacy of EPA add-on beyond that of placebo for residual psychotic, cognitive and affective symptoms in a sample of schizophrenia patients treated with neuroleptics or CLZ [97]. Conversely, adjunctive E-EPA was significantly superior to placebo in improving clinical symptoms and in reducing triglyceride levels in partial-responder schizophrenia patients treated with CLZ, with best results seen at the dose of 2 mg/day [98]. Positive results were also reported by a 12-week RCT, fixed-dose study on schizophrenia patients with persistent symptoms treated with neuroleptics or CLZ: E-EPA addon (3 mg/day) shows a significant advantage over placebo in reducing PANSS scores (primary measure), although data should be interpreted with caution for the small sample of CLZ-treated patients [99]. Regarding safety, E-EPA add-on was well tolerated and did not cause side effects other than mild gastrointestinal symptoms. A 12-week, double-blind, placebo-controlled trial showed that the augmentation with the presynaptic vesicular monoamine transporter inhibitor tetrabenazine was not effective in improving clinical symptoms in a sample of treatmentresistant schizophrenia patients [100]. Minocycline, a second-generation tetracycline characterized by anti-inflammatory and neuroprotective properties, showed beneficial effects on negative symptoms, general outcome and executive functions in a longitudinal RCT on a sample of early phase schizophrenia patients treated with SGAs, including CLZ [101]. Recently, minocycline add-on to CLZ in two treatment-resistant schizophrenia patients was effective in reducing residual positive and negative symptoms [102]. In both studies, minocycline was well tolerated and safe, and 2338

these results warrant further investigation of add-on treatment for patients with schizophrenia.

Augmentation with electroconvulsive therapy

6.

As suggested by several studies [103-105], electroconvulsive therapy (ECT) augmentation of CLZ, in some cases followed by maintenance ECT, could be effective in patients with treatment-resistant schizophrenia, mainly on several classes of symptoms, such as catatonic behavior, aggression and positive symptoms. Nevertheless, it has been highlighted that in many cases such results are limited by unclear reporting of both treatment dosages and by the lacking of CLZ serum levels; this latter issue is particularly relevant, since the effect of ECT on the blood--brain barrier permeability may allows the penetration of greater amounts of CLZ into the brain [25]. Actually, there is not enough evidence to draw definite conclusions regarding this augmentation strategy, as suggested by the review of the available literature on this issue [18]. 7.

Conclusion

The present review focused on available evidence of augmentation strategies for CLZ-resistant patients. The main limitation of the search strategy used in updating the available data on this topic was the focus on publications on CLZ; consequently, many papers on combination and augmentation strategies in schizophrenia in general, where also large cohorts of CLZtreated patients are described, have not been included in the review. Taking into account this limitation, overall data tend to confirm that, despite the extensive use of SGAs, CLZ remains the drug of choice in treatment-resistant schizophrenia, and this option should be tested before considering less-proven therapies. Studies on first-episode patients are still lacking because, due to its risk profile, CLZ is not the firstline choice for treatment of schizophrenia for its association with definite risks such as agranulocytosis, weight gain, metabolic symptoms and cardiac inflammation. Thus, CLZ may be used only after at least two failed previous treatments with two other different APs administered at adequate doses and for sufficient duration. Further limitations of CLZ use are the need of slow dose titration, frequent blood counts and the reduced threshold for seizures when high dose are administered. Side effects such as sedation, hypersalivation and weight gain may compromise patients’ compliance. Although current guidelines recommend that CLZ should be administered to schizophrenia patients with persistent symptoms of hostility, violent behaviors and suicidality [106], evidence has shown that CLZ treatment is consistently underutilized or that the initiation of treatment is frequently delayed. The restriction of CLZ use and the quite diffused attitude of psychiatrists to consider CLZ as the last resort in the treatment of schizophrenia are factors that presumably hamper the efficacy of CLZ




treatment, thus increasing the proportion of patients who are nonresponsive to CLZ treatment [107,108]. It is almost well known that a significant proportion of CLZtreated patients show a partial or inadequate response to treatment, even though their CLZ plasma levels are in the appropriate range. These patients show reduced quality of life, disabling symptoms, poor outcome and a chronic, relapsing course that requires multiple hospitalizations. As a consequence, the treatment of these refractory, highly symptomatic patients still remains a challenge, and it represents a persistent public health burden accounting for the majority of the total health cost of treating schizophrenia [19]. When the optimization of CLZ treatment, in regard to minimizing side effects and improving the rate of response, has failed, any treatment that potentially could improve the quality of life of treatmentrefractory patients should be considered. It is not effortless to establish which can be the appropriate therapy for patients with refractory schizophrenia who show a poor response to CLZ. In clinical practice, CLZ augmentation therapy with additional psychotropic drugs, such as APs, antidepressants and mood stabilizers, as well as other agents, is a common strategy [17,60,107], although not always supported by clear scientific evidence regarding efficacy, safety and tolerability. 8.

Expert opinion

Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. Augmentation with a second AP is one of the most frequently employed strategies for CLZ-resistant patients, both in research samples and in clinical practice, although there is no current consensus regarding this strategy. The Schizophrenia Patient Outcomes Research Team found scarce support for the efficacy and safety of combining CLZ with a second AP [18]. Nevertheless, Taylor and Smith [109] conclude that although the efficacy of augmentation with an additional AP is modest, this strategy deserves further studies, as clinical improvement in subgroups of treatment-resistant schizophrenia patients is possible. It has been hypothesized that APs with high-potency D2 blockade should enhance the efficacy of CLZ, whose mechanism of action is characterized by a weak dopamine D2-antagonism [110]. Nevertheless, data do not support the addition of an AP with high-potency D2 to CLZ, and this is confirmed by the observation that risperidone, the SGA with the strongest D2 blockade, demonstrated poor efficacy and high risk of side effects when added to CLZ [25]. When drugs such as aripiprazole, a partial D2 agonist, and amisulpride, a D3 antagonist, have been added to CLZ, a certain degree of symptoms improvement was seen, thus it seems that increasing the D2 occupation might be ineffective or deleterious rather than beneficial [111]. The antidepressants augmentation of CLZ remains unclear with inconsistencies reported. Drugs with predominant serotonergic effects, such as fluoxetine, have not shown beneficial

effects, whereas mirtazapine and duloxetine add-on showed better results. Only one RCT showed that citalopram was effective on total symptoms severity. The positive effect reported with fluvoxamine add-on may be due to its ability to block sigma receptors [112], although this drug has been shown to inhibit the metabolism of CLZ and its main metabolite, thus increasing CLZ and norclozapine plasma levels; this may further contribute to metabolic adverse effects. Regarding CLZ augmentation with mood stabilizers, the most investigated compounds were lithium, valproate, lamotrigine and topiramate. Whereas lithium plus CLZ shows efficacy in schizoaffective disorder, it appears to be rather ineffective and potentially unsafe in schizophrenia. Augmentation of valproate with CLZ has been evaluated in a single retrospective study [74]; although it was reported as effective during the first month of treatment compared to CLZ monotherapy and CLZ associated with lithium on several symptom cluster (mood, anxiety and hostility), there is no sufficient evidence to advise the use of this augmentation strategy before further investigation in randomized clinical trials. Lamotrigine have shown more encouraging results, although evidence regarding its effective role in ameliorating symptoms in patients with inadequate response to CLZ is still a matter of debate. Although not focused on treatment-refractory samples, further augmentation strategies with other agents have been evaluated. The traditional dopamine/serotonin blockade has been the focus of pharmacotherapy for the past decades; nevertheless, the relatively high number of poor responders to AP treatments poses serious questions on which may be alternative neurotransmitter targets in schizophrenia spectrum disorders. Emerging data indicate that hypofunction of glutamatergic NMDA receptor transmission plays a role in the pathophysiology of schizophrenia [113]; however, glutamatergic agents added to CLZ have not been effective nor have worsened the psychotic symptoms, suggesting that glycinergic drugs interfere with the mechanism of action of CLZ. CX516 was the only positive exception, showing improvement on negative symptoms and total symptom severity, although, as an experimental drug, it may not be suitable as augmentation strategy in clinical practice. On the other hand, considering the differences among glutamatergic drugs, and the complexity of the glutamatergic system, further research is needed to better investigate these strategies. Based on the membrane phospholipid hypothesis of schizophrenia [114], the supplementation of CLZ with E-EPA have shown encouraging, although controversial, results; thus, further studies should clarify the real effectiveness and the best dose of E-EPA add-on. The trials with minocycline add-on treatment to CLZ have shown a promising symptomatic response in schizophrenia patients; these results warrant further research of minocycline add-on therapy for treatment-resistant schizophrenia patients. Considering that augmentation trials may need to be longer than the 4 -- 6 weeks usually recommended for acute AP monotherapy and the risk of long-term polypharmacology,


2339



there is a strong need for further studies adding new and definite knowledge in this field. Taking into account the augmentation treatments reviewed in this paper, although some strategies seem to be encouraging and relatively safe, a possible increase of adverse effects and drug interactions must be considered; moreover, there is still a lack of large RCTs providing strong evidence-based support for CLZ-resistant patients. This is a serious challenge for clinical psychiatry, since what is defined as resistance to AP treatment is currently a primary healthcare burden involving high costs, poor adaptation to the demands of daily life and deterioration in social adjustment. The heterogeneity in treatment response, which is associated with a number of factors, such as poor compliance, individual differences in metabolism, comorbidity, substance abuse and lack of psychosocial support, is a feature of the diseases that are included within the diagnostic category of schizophrenia. There is increasing evidence that subtypes of schizophrenia with possibly different pathophysiology exist and that the categorical entity named schizophrenia may lack diagnostic specificity [24]. It must also be recognized that the prognosis for schizophrenia has not changed fundamentally since the introduction of FGAs [115]. Moreover, psychotic symptoms are not specific to schizophrenia, and this would suggest that the dopamine system, although fundamental in the pathogenesis of psychosis, may not be so central to schizophrenia as traditionally claimed. Current evidence has shown that genes conferring high risk of schizophrenia are mainly related to synaptic and glia functions, neuronal growth and cortical microcircuitry neurodevelopment, whereas they do not code for dopamine system [116]. Further, children at risk of schizophrenia show developmental delays, mainly in the social domain, and postmortem neuropathological studies have suggested that schizophrenia is associated with abnormal early neurodevelopment affecting neuronal migration, survival and connectivity [117]. From a therapeutic point of view, it is almost clear that we are living a phase of stagnation characterized by the

2340

marketing of different depot formulations of existing APs in order to improve treatment adherence and compliance, whereas research on new drugs is still lacking. It has been suggested that several factors may affect research on new treatments, especially the single disease paradigm of schizophrenia, the difficulty to improve translational tools to facilitate preclinical drug discovery and the complexity to identify alternative neurotransmitter pathways as treatment targets [24]. Current and future progresses in genetic polymorphisms, biomarker identification and diagnostic imaging may contribute to exploring treatment approaches that are increasingly specific, which may target underlying pathogenetic pathways. Advances in genomic research on large cohorts of schizophrenia subjects may lead to a better understanding of the heterogeneity of the disease, with the ultimate goal of identifying those genotypes and genetic variants that are probably associated with treatment outcome. Within this context, treatmentrefractory schizophrenia should be specifically addressed as a possible phenotype in genome-wide association studies with the aim of identifying definite genetic susceptibility for individualized treatment and possibly to make reliable predictions on the efficacy and tolerability of AP treatment. Finally, more research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and the challenge of facing those core schizophrenia symptoms, such as negative and cognitive symptoms, and social functioning and cognition that mainly contribute to the public health burden of treatment-resistant schizophrenia.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.



Bibliography

symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol 2004;24:225-8

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


1.

2.

3.

4.

5.

6.

7.

..

Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 2012;13:318-78 Kane J, Honingfeld G, Singer J, Meltzer H. Clozapine for the treatment resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96 Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10:799-812 Tsang HW, Leung AY, Chung RC, et al. Review on vocational predictors: a systematic review of predictors of vocational outcomes among individuals with schizophrenia: an update since 1998. Aust N Z J Psychiatry 2010;44:495-504 Suzuki T, Remington G, Mulsant BH, et al. Treatment resistant schizophrenia and response to antipsychotics: a review. Schizophr Res 2011;133:54-62 Bell MD, Corbera S, Johannesen JK, et al. Social cognitive impairments and negative symptoms in schizophrenia: are there subtypes with distinct functional correlates? Schizophr Bull 2013;39:186-96 Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951-62 An excellent, outstanding meta-analysis of second-generation antipsychotic drugs (APs).

8.

Lieberman JA, Safferman AZ, Pollack S, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994;151:1744-52

9.

Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: international Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60:82-91

10.

Volavka J, Czobor P, Nolan K, et al. Overt aggression and psychotic

11.

Chakos M, Lieberman J, Hoffman E, et al. Effectiveness of second-generation antipsychotics in patients with treatmentresistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001;158:518-26

12.

Dold M, Leucht S. Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective. Evid Based Ment Health 2014;17:33-7 A fundamental and up-to-date clinical review on evidence-based treatment strategies in treatmentresistant schizophrenia.

..

13.

14.

..

Ulrich S, Baumann B, Wolf R, et al. Therapeutic drug monitoring of clozapine and relapse -- a retrospective study of routine clinical data. Int J Clin Pharmacol Ther 2003;41:3-13 Conley RR, Carpenter WT Jr, Tamminga CA. Time to clozapine response in a standardized trial. Am J Psychiatry 1997;154:1243-7 This important paper provides evidence on the time needed to obtain clinical response during clozapine (CLZ) treatment.

recommendations and summary statements. Schizophr Bull 2010;36:71-93 19.

Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 2012;38:1003-11

20.

McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163:600-10

21.

Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40

22.

Remington G, Saha A, Chong SA, Shammi C. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005;19:843-72

23.

Mouaffak F, Tranulis C, Gourevitch R, et al. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin Neuropharmacol 2006;29:28-33 An interesting review focused on ultraresistant schizophrenia.

.

15.

Sherwood M, Thornton AE, Honer WG. A quantitative review of the profile and time course of symptom change in schizophrenia treated with clozapine. J Psychopharmacol 2012;26:1175-84

24.

Van Sant SP, Buckley PF. Pharmacotherapy for treatment-refractory schizophrenia. Expert Opin Pharmacother 2011;12:411-34

16.

Nielsen J, Damkier P, Lublin H, Taylor D. Optimizing clozapine treatment. Acta Psychiatr Scand 2011;123:411-22 This paper provides detailed information on CLZ optimization in order to increase the rate of response and to minimize side effects.

25.

Porcelli S, Balzarro B, Serretti A. Clozapine resistance: augmentation strategies. Eur Neuropsychopharmacol 2012;22:165-82 An excellent and up-to-date review and meta-analysis of CLZ augmentation strategies.

..

17.

..

18.

Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev 2009(3):CD006324 An excellent Cochrane review of CLZ combination with APs for the treatment of schizophrenia. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment


..

26.

Anil Yag˘ciog˘lu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72

27.

Josiassen RC, Joseph A, Kohegyi E, et al. A clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebocontrolled trial. Am J Psychiatry 2005;162:130-6

2341


28.

29.


30.

31.

32.

33.

34.

35.

36.

37.

2342

Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354:472-82 Akdede BB, Anil Yag˘ciog˘lu AE, Alptekin K, et al. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry 2006;67:1912-19 Freudenreich O, Henderson DC, Walsh JP, et al. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res 2007;92:90-4 Weiner E, Conley RR, Ball MP, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology 2010;35:2274-83 Kuwilsky A, Krumm B, Englisch S, et al. Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry 2010;43:216-20 Chang JS, Ahn YM, Park HJ, et al. Aripiprazole augmentation in clozapinetreated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008;69:720-31 Bachmann CJ, Lehr D, Theisen FM, et al. Aripiprazole as an adjunct to clozapine therapy in adolescents with early-onset schizophrenia: a retrospective chart review. Pharmacopsychiatry 2009;42:153-7

blind, placebo-controlled study. Schizophr Res 2011;127:93-9 38.

39.

Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebocontrolled study. Br J Psychiatry 1997;171:569-73

40.

Agelink MW, Kavuk I, Ak I. Clozapine with amisulpride for refractory schizophrenia. Am J Psychiatry 2004;161:924-5

41.

Kampf P, Angelink MW, Naber D. Augmentation of clozapine with amisulpride: a promising therapeutic approach to refractory schizophrenic symptoms. Pharmacopsychiatry 2005;38:39-40

42.

43.

44.

Fleischacker WW, Heikkinen ME, Olie JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010;12:1115-25

45.

Benedetti A, Di Paolo A, Lastella M, et al. Augmentation of clozapine with aripiprazole in severe psychotic bipolar and schizoaffective disorders: a pilot study. Clin Pract Epidemiol Ment Health 2010;6:30-5

46.

Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-

Cipriani A, Accordini S, Nose` M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12month, randomized, naturalistic trial. J Clin Psychopharmacol 2013;33:533-7

Munro J, Matthiasson P, Osborne S, et al. Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine. Acta Psychiatr Scand 2004;10:292-8 Genç Y, Taner E, Candansayar S. Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a singleblind randomized study. Adv Ther 2007;24:1-13 Assion HJ, Reinbold H, Lemanski S, et al. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebocontrolled trial. Pharmacopsychiatry 2008;41:24-8 Hotham JE, Simpson PJ, Brooman-White RS, et al. Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital. CNS Spectr 2013;28:1-8 Zink M, Kuwilsky A, Krumm B, et al. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Psychopharmacol 2009;23:305-14


47.

Kuwilsky A, Krumm B, Englisch S, et al. Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry 2010;43:216-20

48.

Muscatello MR, Pandolfo G, Mico` U, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2014;34:129-33

49.

Friedman JI, Lindenmayer JP, Alcantara F, et al. Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology 2011;36:1289-95

50.

Gunduz-Bruce H, Oliver S, Gueorguieva R, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res 2013;143:344-7

51.

Nielsen J, Emborg C, Gydesen S, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebocontrolled study. J Clin Psychopharmacol 2012;32:173-8

52.

Flynn SW, Altman S, MacEwan GW, et al. Prolongation of clozapine-induced granulocytopenia associated with olanzapine. J Clin Psychopharmacol 1997;17:494-5

53.

Gupta S, Sonnenberg SJ, Frank B. Olanzapine augmentation of clozapine. Ann Clin Psychiatry 1998;10:113-15

54.

Buoli M, Dobrea C, Caldiroli A, et al. Augmentative asenapine in a recurrent manic catatonic patient with partial response to clozapine. Case Rep Psychiatry 2013;2013:503601

55.

Paraschakis A. Pipamperone augmentation of clozapine and sodium valproate in refractory schizophrenia: a case report. Clin Neuropharmacol 2014;37:60-1

56.

Hou YC. Improvement in psychotic symptoms and social functioning after augmentation of paliperidone with clozapine in a patient with schizoaffective disorder. J Neuropsychiatry Clin Neurosci 2014;26:E26

57.

Henderson DC, Fan X, Copeland PM, et al. Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia. Hum Psychopharmacol 2009;24:225-32


58.

59.


60.

..

68.

78.

Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophrenia Res 2010;123:225-33

Delle Chiaie R, Salviati M, Fiorentini S, Biondi M. Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol 2007;15:563-8

Tiihonen J, Hallikainen T, Ryynanen OP, et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo- controlled crossover trial. Biol Psychiatry 2003;54:1241-8

69.

Mico` U, Bruno A, Pandolfo G, et al. Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial. Int Clin Psychopharmacol 2011;26:303-10

79.

Zoccali R, Muscatello MR, Bruno A, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res 2007;93:109-16

70.

Santoro V, D’Arrigo C, Spina E, et al. Effect of adjunctive duloxetine on the plasma concentrations of clozapine, olanzapine, and risperidone in patients with psychotic disorders. J Clin Psychopharmacol 2010;30:634-6

80.

Vayısog˘lu S, Anıl Yag˘cıog˘lu AE, Yag˘cıog˘lu S, et al. Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment. Schizophr Res 2013;143:207-14

71.

Bruno A, Zoccali RA, Abenavoli E, et al. Augmentation of clozapine with agomelatine in partial-responder schizophrenia: a 16-week, open-label, uncontrolled pilot study. J Clin Psychopharmacol 2014;34:491-4

81.

72.

Small JG, Klapper MH, Malloy FW, et al. Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol 2003;23:223-8

Spina E, D’Arrigo C, Migliardi G, et al. Effect of adjunctive lamotrigine treatment on the plasma concentrations of clozapine, risperidone and olanzapine in patients with schizophrenia or bipolar disorder. Ther Drug Monit 2006;28:599-602

82.

Tiihonen J, Halonen P, Wahlbeck K. Topiramate add-on in treatment-resistant schizophrenia: a randomized, doubleblind, placebo-controlled, crossover trial. J Clin Psychiatry 2005;66:1012-15

Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 2010;197:174-9 Outstanding meta-analysis on antidepressant for the treatment of negative symptoms.

61.

Buchanan RW, Kirkpatrick B, Bryant N, et al. Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 1996;153:1625-7

62.

Spina E, Avenoso A, Facciola G, et al. Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Int Clin Psychopharmacol 1998;13:141-5

63.

Anghelescu I, Szegedi A, Schlegel S, et al. Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial. Eur Neuropsychopharmacol 1998;8:315-20

64.

Lu ML, Lane HY, Chen KP, et al. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry 2000;61:594-9

65.

Lu ML, Lane HY, Lin SK, et al. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry 2004;65:766-71

66.

Lan GX, Li ZC, Li L. A randomized, placebo-controlled clinical trial of combined citalopram and clozapine in the treatment of negative symptoms of schizophrenia. Chin Ment Health J 2006;20:696-8

67.

controlled trials. J Clin Psychopharmacol 2007;27:582-9

controlled study. Int Clin Psychopharmacol 2004;19:71-6

Muscatello MRA, Bruno A, Pandolfo G, et al. Topiramate augmentation of clozapine in schizophrenia: a doubleblind, placebo-controlled study. J Psychopharmacol 2010;25:667-74

Zoccali R, Muscatello MR, Cedro C, et al. The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-

73.

Bender S, Linka T, Wolstein J, et al. Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol 2004;7:59-63

83.

Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double blind, placebo-controlled clinical trial. J Psychopharmacol 2008;23:157-62

74.

Kelly DL, Conley RR, Feldman S, et al. Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia. Psychiatr Q 2006;77:81-95

84.

Behdani F, Hebrani P, Rezaei Ardani A, Rafee E. Effect of topiramate augmentation in chronic schizophrenia: a placebo-controlled trial. Arch Iran Med 2011;14:270-5

75.

Dursun SM, Deakin JFW. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatmentresistant schizophrenia: a naturalistic case--series outcome studies. J Psychopharmacol 2001;15:297-301

85.

Hahn MK, Cohn T, Teo C, et al. Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters. Clin Schizophr Relat Psychoses 2013;6:186-96

86.

76.

Kremer I, Vass A, Gorelik I, et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol Psychiatry 2004;56:441-6

Potkin SG, Jin Y, Bunney BG, et al. Effect of clozapine and adjunctive highdose glycine in treatment-resistant schizophrenia. Am J Psychiatry 1999;156:145-7

87.

77.

Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-

Diaz P, Bhaskara S, Dursun SM, Deakin B. Double-blind, placebocontrolled, crossover trial of clozapine plus glycine in refractory schizophrenia


2343


study of the effects of ethyleicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002;36:7-18

negative results. J Clin Psychopharmacol 2005;25:277-8 88.


89.

Heresco-Levy U, Javitt DC, Ermilov M, et al. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999;56:29-36 Evins AE, Fitzgerald SM, Wine L, et al. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 2000;157:826-8

90.

Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 1999;45:512-14

91.

Goff DC, Tsai G, Manoach DS, et al. D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 1996;153:1628-30

92.

Tsai GE, Yang P, Chung LC, et al. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 1999;156:1822-5

93.

94.

95.

96.

97.

98.

2344

Lane HY, Huang CL, Wu PL, et al. Glycine transporter I inhibitor, Nmethylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006;60:645-9 Goff DC, Leahy L, Berman I, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001;21:484-7 de Lucena D, Fernandes BS, Berk M, et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry 2009;70:1416-23 Stryjer R, Strous R, Bar F, et al. Donepezil augmentation of clozapine monotherapy in schizophrenia patients: a double blind cross-over study. Hum Psychopharmacol 2004;19:343-6 Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001;158:2071-4

99.

Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. Randomized, placebocontrolled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002;159:1596-8

.

world’. Acta Psychiatr Scand 2012;126:40-6 An interesting cross-sectional study on CLZ augmentation strategies in clinical settings.

108. Remington G, Agid O, Foussias G, et al. Clozapine’s role in the treatment of firstepisode schizophrenia. Am J Psychiatry 2013;170:146-51

100. Remington G, Kapur S, Foussias G, et al. Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12week, double-blind, placebo-controlled trial. J Clin Psychopharmacol 2012;32:95-9

109. Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic -- a meta-analysis of randomized, placebocontrolled studies. Acta Psychiatr Scand 2009;119:419-25 .. A fundamental meta-analysis evaluating APs augmentation of CLZ.

101. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010;71:138-49

110. Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur Psychiatry 2005;20:409-15

102. Qurashi I, Collins J, Chaudhry I, Husain N. Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia. J Psychopharmacol 2014;28:707-8

111. Giegling I, Drago A, Scha¨fer M, et al. Interaction of haloperidol plasma level and antipsychotic effect in early phases of acute psychosis treatment. J Psychiatr Res 2010;44:487-92

103. Kho KH, Blansjaar BA, de Vries S, et al. Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia - an open label study. Eur Arch Psychiatry Clin Neurosci 2004;254:372-9

112. Hindmarch I, Hashimoto K. Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Hum Psychopharmacol 2010;25:193-200

104. Havaki-Kontaxaki BJ, Ferentinos PP, Kontaxakis VP, et al. Concurrent administration of clozapine and electroconvulsive therapy in clozapineresistant schizophrenia. Clin Neuropharmacol 2006;29:52-6 105. Masoudzadeh A, Khalilian AR. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatmentresistant schizophrenic patients. Pak J Biol Sci 2007;10:4287-90 106. Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB. The schizophrenia patient outcomes research team (PORT): updated treatment recommendations 2009. Schizophr Bull 2010;36:94-103 107. Pai NB, Laidlaw M, Vella SC. Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia in the ’real

Peet M, Horrobin DF; E-E Multicentre Study Group. A dose-ranging exploratory


113. Pollak TA, McCormack R, Peakman M, et al. Prevalence of anti-N-methyl-daspartate (NMDA) antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med 2013;13:1-13 114. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998;30:193-208 115. Molina JD, Jimenez-Gonza´lez AB, Lo´pez-Munõz F, Canãs F. Evolution of the concept of treatment-resistant schizophrenia: toward a reformulation for lack of an adequate response. J Exp Clin Med 2012;4:98-102 116. Geyer MA, Olivier B, Joe¨ls M, Kahn RS. From antipsychotic to anti-schizophrenia drugs: role of animal models. Trends Pharmacol Sci 2012;33:515-21 117. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of


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their convergence. Mol Psychiatry 2005;10:40-68 This paper provides insightful evidence on genetics and neurobiology of schizophrenia.


Affiliation

Maria Rosaria A Muscatello†1 MD PhD, Antonio Bruno1 MD PhD, Pasquale De Fazio2 MD, Cristina Segura-Garcia2 MD, Gianluca Pandolfo1 MD PhD & Rocco Zoccali3 MD † Author for correspondence 1 University of Messina, Department of Neurosciences, Policlinico Universitario Via Consolare Valeria -- Messina 98125, Italy Tel: +39 090 22212092; Fax: +39 090 695136; E-mail: [email protected] 2 University Magna Graecia of Catanzaro, Department of Health Sciences, Catanzaro, Italy 3 Professor, University of Messina, Department of Neurosciences, Messina, Italy


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Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.

Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine.

Pro-inflammatory cytokine levels are raised in female schizophrenia patients treated with clozapine.

Obesity correlates with fewer symptoms in schizophrenia treated with long-term clozapine: gender difference.

Weight gain among schizophrenic patients treated with clozapine.

Treatment of Hypochondriasis in Two Schizophrenia Patients Using Clozapine.

Outcomes of medicaid beneficiaries with schizophrenia receiving clozapine only or antipsychotic combinations.

Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine.

Clozapine induced tubulointerstitial nephritis in a patient with paranoid schizophrenia.

Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia.

Hormonal response to fenfluramine challenges in clozapine-treated schizophrenic patients.

Clozapine for the treatment of adolescents with schizophrenia.

Clozapine response in early treatment-resistant schizophrenia.

Effectiveness and safety of clozapine in elderly patients with chronic resistant schizophrenia.

Determination of clozapine in serum of patients with schizophrenia as a measurement of medication compliance.

Effect of Adenine on Clozapine-induced Neutropenia in Patients with Schizophrenia: A Preliminary Study.

Metformin for treatment of clozapine-induced weight gain in adult patients with schizophrenia: a meta-analysis.

Effect of clozapine on white matter integrity in patients with schizophrenia: a diffusion tensor imaging study.

Sodium nitroprusside treatment of clozapine-refractory schizophrenia.

Clozapine and risperidone influence on cortisol and estradiol levels in male patients with schizophrenia.

Clozapine-induced seizures, electroencephalography abnormalities, and clinical responses in Japanese patients with schizophrenia.

A randomized trial of clozapine vs. other antipsychotics for cannabis use disorder in patients with schizophrenia.

Serum levels of PYY(1-36) peptide in patients with schizophrenia on clozapine monotherapy.

An association between autumn birth and clozapine treatment in patients with schizophrenia: a population-based analysis.