Clozapine resistant schizophrenia: Newer avenues of management

Table 1 Key components of the current definitions of clozapine-resistant schizophrenia[12,14-16]

Diagnosis	Diagnosis of schizophrenia using standardized criteria and after ruling out psychosis due to substance use or medical conditions
Adequate clozapine treatment
Dose	200-500 mg/d
Blood levels	≥ 350 ng/mL
Treatment duration	2-3 mo1
Treatment adherence	≥ 80% of prescribed doses for the duration of treatment
Response to clozapine
Baseline symptom severity and functional impairment	Moderately severe illness either globally or in positive and negative symptom domains assessed using standardized scales (CGI, BPRS, PANSS, SAPS, SANS). Moderate levels of functional impairment assessed using standardized scales (GAF, SOFAS)
Non-response	< 20% reduction in symptoms and minimal response in levels of functional impairment during an adequate trial of clozapine treatment
Persistence	Moderately severe illness and functional impairment should persist following an adequate trial of clozapine treatment

¹It has been proposed that duration of clozapine trials should be 2 mo for patients with aggression or self-harm, 3 mo for those with positive symptoms, and 4 mo for those with negative and cognitive symptoms[13].

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression scale; GAF: Global Assessment of Functioning scale; PANSS: Positive and Negative Syndrome Scale; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms; SOFAS: Social and Occupational Functioning Scale.

Table 2 Reviews of antipsychotic augmentation strategies in clozapine-resistant schizophrenia¹

Ref.	Type of review	Details	Effect on positive or psychotic symptoms	Effect on negative or depressive symptoms
Wagner et al[2], 2019	Systematic review	14 meta-analyses of FGA and SGA augmentation of clozapine.	Some evidence of benefits based on low-quality studies (SIGN grade B).
Roerig et al[8], 2019	Systematic review	4 meta-analyses and 1 naturalistic study of FGA and SGA augmentation of clozapine.	No benefits of antipsychotics when high-quality RCTs were considered.
Bartoli et al[22], 2019	Meta-analysis	12 RCTs of SGA augmentation of clozapine-risperidone (n = 5) and aripiprazole (n = 3).	No difference between SGA augmentation and placebo in improving positive symptoms.	A small benefit of SGA augmentation for negative and depressive symptoms.
Siskind et al[23], 2018	Meta-analysis	19 RCTs of FGA and SGA augmentation of clozapine-aripiprazole (n = 7), risperidone (n = 3), and amisulpiride (n = 2).	Evidence for benefit with aripiprazole, but effects were lost when low-quality studies were excluded.
Correll et al[24], 2017	Meta-analysis	Meta-analysis of 29 previous meta-analyses of antipsychotic combinations-5 clozapine combinations examined.	Clozapine combinations no different from clozapine monotherapy for positive symptoms.	Clozapine combinations no different from clozapine monotherapy for negative symptoms.
Galling et al[25], 2017	Meta-analysis	20 RCTs of FGA and SGA augmentation of clozapine-risperidone (n = 6) and aripiprazole (n = 6).	No evidence for additional benefits of augmentation in double-blind, high-quality RCTs.	Improvement in negative symptoms with aripiprazole augmentation. No effect of augmentation on depressive symptoms.
Ortiz-Orendain et al[26], 2017	Meta-analysis	31 RCTs and quasi-RCTs of augmentation with SGAs (n = 26) and FGAs (n = 5) including clozapine augmentation.	Low-quality evidence that augmentation improves global clinical response. No specific effects on positive symptoms.	No effect of augmentation on negative symptoms.
Barber et al[27], 2017	Meta-analysis	5 RCTs of clozapine augmentation with SGAs or haloperidol.	Low-quality evidence that augmentation may improve global clinical response. Effects on positive symptoms not clear.	Effects on negative symptoms not clear.
Jiménez-Cornejo et al[28], 2016	Meta-analysis	17 prior meta-analyses and reviews of FGA and SGA augmentation (62 studies) of clozapine.	Little evidence that augmentation improves clinical response (> 20% reduction in PANSS/BPRS scores).
Taylor et al[29], 2012	Meta-analysis	14 RCTs of FGA and SGA augmentation of clozapine.	A small benefit in overall symptom reduction with augmentation.
Sommer et al[30], 2012	Meta-analysis	10 RCTs of FGA and SGA augmentation of clozapine.	One RCT showed that sulpiride augmentation led to overall symptom reduction. No specific effects on positive symptoms.	No specific effects on negative symptoms.
Porcelli et al[31], 2012	Systematic review and meta-analysis	Systematic review of 25 studies of SGA augmentation of clozapine - risperidone (11 trials) and aripiprazole (6 trials). Meta-analysis of 5 RCTs of risperidone augmentation of clozapine.	Low quality evidence indicated benefits for aripiprazole and amisulpiride augmentation. No benefit of risperidone augmentation.	Some benefit of aripiprazole in reducing negative symptoms from 1 RCT.

¹Several other systematic reviews[9,12,14,32,33] and meta-analyses[17,34-37] have been unable to find significant benefits, while others have reported modest benefits for antipsychotic augmentation of clozapine[38-44].

BPRS: Brief Psychiatric Rating Scale; FGA: First-generation antipsychotic; RCT: Randomized controlled trial; PANSS: Positive and Negative Syndrome Scale; SGA: Second-generation antipsychotic; SIGN: Scottish Intercollegiate Guidelines Network.

Table 3 Meta-analyses of antidepressant and mood stabilizer augmentation in clozapine-resistant schizophrenia

Ref.	Type of review	Details	Results
Antidepressants
Siskind et al[23], 2018	Meta-analysis	10 RCTs of fluoxetine, paroxetine, duloxetine, and mirtazapine augmentation	Some evidence for fluoxetine augmentation in reducing in overall symptom severity based on 1 high-quality RCT.
Correll et al[24], 2017	Meta-analysis	Analysis based on the earlier meta-analysis of Veerman et al[37]	No benefit of antidepressant augmentation on reduction in overall, positive, and negative symptom severity.
Veerman et al[37], 2014	Meta-analysis	4 RCTs of mirtazapine, duloxetine, and fluoxetine augmentation	No benefit of antidepressant augmentation on reduction in overall, positive, and negative symptom severity.
Sommer et al[30], 2012	Meta-analysis	4 RCTs of mirtazapine, citalopram, and fluoxetine augmentation	Some evidence for citalopram augmentation in reducing overall and negative symptom severity based on 1 RCT.
Mood stabilizers
Siskind et al[23], 2018	Meta-analysis	5 RCTs of valproate (n = 2), lamotrigine (n = 2), lithium (n = 1), and topiramate(n = 1) augmentation	Low-quality evidence for valproate and lithium augmentation in reducing total symptom severity. Reduction of positive and negative symptom severity by topiramate augmentation based on1 RCT.
Correll et al[24], 2017	Meta-analysis	Analysis based on the earlier meta-analysis of Veerman et al[37]	No benefit of lamotrigine and topiramate augmentation on reduction in overall, positive, and negative symptom severity.
Zheng et al[50], 2017	Meta-analysis	22 RCTs of valproate (n = 9), lamotrigine (n = 8), and topiramate (n = 4) augmentation	Significant benefits for valproate and topiramate in reducing total and positive symptom severity but based on low-quality studies. No effects on clinical response.
Zheng et al[48], 2016	Meta-analysis	4 RCTs of topiramate augmentation	Significant benefits of topiramate augmentation in reducing overall, positive, and negative symptom severity.
Veerman et al[49], 2014	Meta-analysis	6 RCTs of lamotrigine and 4 RCTs of topiramate augmentation	No benefit of lamotrigine and topiramate augmentation on reduction in overall, positive, and negative symptom severity.
Sommer et al[30], 2012	Meta-analysis	7 RCTs of lamotrigine (n = 4) and topiramate (n = 3) augmentation	Benefits of lamotrigine and topiramate augmentation for total and positive symptoms based on single RCTs that did not persist on further analysis.
Tiihonen et al[47], 2009	Meta-analysis	5 RCTs of lamotrigine augmentation	Evidence for benefit of lamotrigine augmentation in reducing overall, positive, and negative symptom severity.

RCT: Randomized controlled trial.

Table 4 Electroconvulsive therapy and recurrent transcranial magnetic stimulation augmentation in clozapine-resistant schizophrenia

ECT
Ref.	Study/review	Details	Results
Masoudzadeh et al[56], 2007	Controlled trial, (non-randomized, non-blinded)	18 patients with TRS; 3 groups of clozapine-ECT treatment, only clozapine and only ECT treatment (n = 6 each)	Significant differences between the clozapine- ECT combination and monotherapy groups in reduction of PANSS scores.
Petrides et al[54], 2015	Single-blind cross-over RCT	39 patients with TRS randomized to clozapine-ECT (n = 20) and clozapine only treatment (n = 19)	Significantly greater response on BPRS psychosis & CGI scores in the clozapine-ECT combination group.
Melzer-Ribeiro et al[55], 2017	Single-blind sham-controlled RCT	23 patients with CRS randomized to treatment with clozapine-ECT (n = 13) and clozapine-sham ECT (n = 10)	No significant differences between the groups on PANSS total and positive symptom scores and CGI scores.
Kupchik et al[57], 2000	Systematic review	Case reports of 36 patients with TRS and clozapine non-responders	67% of the patients on the clozapine-ECT combination showed good response.
Braga et al[58], 2005	Systematic review	12 case reports or chart reviews of patients with TRS and clozapine non-responders	The clozapine-ECT combination was efficacious.
Havaki-Kontaxaki et al[59], 2006	Systematic review	One open trial and 6 case studies of patients with CRS	73% patients on the clozapine-ECT combination showed marked improvement.
Pompili et al[60], 2013	Systematic review	31 studies examining indications for ECT in schizophrenia	The clozapine-ECT combination was efficacious in patients resistant to medications.
Grover et al[61], 2015	Systematic review	40 studies, mainly case reports of patients with CRS	Short-term response rates of the clozapine-ECT combination varied from 37%-100%.
Lally et al[62], 2016	Systematic review and meta-analysis	Pooled analysis of patients with TRS treated with clozapine and ECT based on 4 open trials, 2 controlled trials (1 RCT)1, 2 chart reviews, 6 case series, and 15 case reports	Pooled response rate with the clozapine-ECT combination was 54% on meta-analysis. Systematic review showed 76% overall response rate with clozapine-ECT treatment and a relapse rate of 32%.
Manubens et al[63], 2016	Systematic review and meta-analysis	6 systematic reviews of ECT in TRS including 6 controlled trials of the clozapine-ECT combination in clozapine non-responders (1 RCT)1	Modest effect of ECT in augmenting clozapine response with low certainty of evidence.
Ahmed et al[64], 2017	Systematic review and meta-analysis	9 studies of the clozapine-ECT combination in TRS including 2 controlled trials (1 RCT)1, 3 open trials, and 4 case series/chart-reviews vs 9 studies of ECT-non-clozapine antipsychotic combination	The ECT-clozapine combination was significantly better than the ECT-non-clozapine antipsychotic combinations in reducing positive symptoms on the PANSS and the BPRS.
Wang et al[52], 2018	Meta-analysis	18 RCTs of clozapine augmentation in CRS (17 from China and 1 from the United States1)	Adjunctive ECT was superior to clozapine monotherapy in reducing positive symptoms after 1–2 wk but with moderate effect size.
rTMS
Wagner et al[66], 2020	Meta-analysis	Pooled data from 10 RCTs for 131 patients with persistent positive and negative symptoms being treated with clozapine	No differences between active and sham rTMS in improving clinical response and reducing PANSS scores. No benefit of rTMS augmentation for patients with persistent symptoms on clozapine.

¹The RCT from United States is by Petrides et al[54].

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression scale; CRS: Clozapine-resistant schizophrenia; ECT: Electroconvulsive therapy; PANSS: Positive and Negative Syndrome Scale; RCT: Randomized controlled trial; rTMS: Recurrent transcranial magnetic stimulation; TRS: Treatment resistant schizophrenia.

Table 5 Psychosocial augmentation strategies in clozapine-resistant schizophrenia

Ref.	Study/participants	Interventions	Results
Studies
Pinto et al[69], 1999	Single-blind RCT of 41 patients with TRS started on clozapine	CBT and social skills training vs supportive therapy for 6 mo.	Significant reductions in positive and negative symptom severity in the CBT group.
Buchain et al[70], 2003	Single-blind RCT of 41 patients with TRS started on clozapine	Occupational therapy and clozapine vs clozapine alone for 6 mo.	Significant improvements in the occupational performance and interpersonal relationships with OT.
Barretto et al[71], 2009	Single-blind RCT of 21 patients with CRS	CBT vs supportive treatment (“befriending”) for 21 wk.	Significant reductions in overall symptom severity and improvement in quality of life with CBT.
Morrison et al[75], 2018	Double-blind RCT of 425 patients with CRS	CBT vs usual treatment for 9 mo. Follow-up for 21 mo.	Significant reductions in PANSS scores with CBT at 9 mo but no differences at 21 mo.
Sensky et al[72], 2000; Valmaggia et al[73], 2005; Edwards et al[74], 2011	RCTs of patients with TRS (n = 48-90) including patients on clozapine or clozapine non-responders	CBT vs supportive treatment or clozapine alone or comparisons with combinations of CBT with other antipsychotics.	Significant reductions in positive, negative, and depressive symptom severity, improvement in clinical response and functioning with CBT; benefits at end of treatment usually maintained during follow-up.
Reviews
Ranasinghe et al[33], 2014	Systematic review	Review of the 2 CBT and 1 OT trial mentioned above.	Benefits of psychosocial interventions noted for overall symptom severity, quality of life, and social functioning.
Polese et al[68], 2019	Systematic review & meta-analysis	Review of all the above trials and meta-analysis of 4 RCTs including Morrison et al[75].	Benefits of psychosocial interventions noted for overall and positive symptom severity.

CBT: Cognitive-behavioural therapy; CRS: Clozapine resistant schizophrenia; PANSS: Positive and Negative Syndrome Scale; OT: Occupational therapy; TRS: Treatment resistant schizophrenia; RCT: Randomized controlled trial.

Table 6 Augmentation of clozapine with long-acting antipsychotic injections in clozapine-resistant schizophrenia

Ref.	Study details	Results
Kim et al[92], 2010	4 patients treated with clozapine and risperidone LAI for 1 yr	Reduction in number and length of hospitalizations and improvement in social skills after LAI addition. Fewer side effects with the combination.
Malla et al[93], 2013	One patient with poor response to clozapine treated with clozapine and an LAI	Improvement in symptoms and social functioning without any increase in side effects with combination treatment.
Baruch et al[94], 2014	8 patients, 6 with TRS. Treated with olanzapine LAI and clozapine or other antipsychotics up to 2 yr	Reduction in aggression in all 8 patients and in symptom severity in 6 patients.
Maia-de-Oliveira et al[95], 2015	2 patients with CRS treated with clozapine and paliperidone LAI for 9-10 mo	Remission of positive symptoms after LAI augmentation.
Kasinathan et al[96], 2016	9 patients with TRS and comorbid personality disorders/substance use and violence; 1 on clozapine but non-adherent treated with olanzapine LAI combination	1 yr of retrospective pre- and post-LAI comparisons showed significant improvements in psychotic symptoms, violence, and reduction in number and length of hospitalizations and emergency visits.
Sepede et al[97], 2016	One patient with poor response to clozapine treated with clozapine and aripiprazole LAI for 1 yr	Symptoms reduced by 50% with the combination without any increase in side effects.
Oriolo et al[98], 2016	Retrospective observational of 23 patients with TRS in whom paliperidone LAI was added toclozapine	Significant reductions in severity of global, positive, negative, depressive, and cognitive symptoms with the combination. Significantly lower doses of clozapine and paliperidone LAI required with combination treatment vs monotherapy.
Souaiby et al[99], 2017	Retrospective observational study with a mirror-image design of 20 patients with TRS treated with clozapine and LAIs for 32 mo	Significant reductions in number and length of hospitalizations during 32 mo of combination treatment vs 1 yr of monotherapy. No increase in side effects with the combination.
Grimminck et al[100], 2020	Retrospective observational study with a mirror- image design of 20 patients with poor response to clozapine or LAIs treated with clozapine and LAI combinations for 2 yr	Significant reductions in hospital admissions and emergency visits during 2 yr of combination treatment vs 2 yr of monotherapy. Overall improvement in behaviour and social functioning but no change in symptoms.
Bioque et al[101], 2020	Retrospective observational study with a mirror- image design of 50 patients with TRS treated with clozapine and paliperidone LAI for 6 mo	Significant reductions in BPRS scores, emergency visits, number and length of hospitalizations, and number and severity of adverse effects as well as significant improvements in social functioning during 6 mo of combination treatment vs 6 mo of monotherapy.
Caliskan et al[102], 2021	Retrospective observational study with a mirror- image design in 29 patients with TRS treated with clozapine and LAI combinations for 1 yr	Significant reductions in number of relapses and number and length of hospitalizations during 1 yr of combination treatment vs 1 yr of monotherapy. No differences in side effects with the combinations.

BPRS: Brief Psychiatric Rating Scale; CRS: Clozapine resistant schizophrenia; LAI: Long-acting antipsychotic injection; TRS: Treatment resistant schizophrenia.

Table 7 Scandinavian nationwide cohort studies of antipsychotic treatment

Ref.	Study details	Results
Tiihonen et al[105], 2006, Finland	2230 inpatients followed up for 3.6 yr	Significantly lower risks of rehospitalization or treatment discontinuation in patients on perphenazine LAI, clozapine, or olanzapine vs those on oral haloperidol.
Tiihonen et al[106], 2009, Finland	66881 outpatients followed up for 11 yr	Clozapine was associated with a substantially lower mortality than any other antipsychotics singly or in combination, with perphenazine as a comparator.
Tiihonen et al[107], 2011, Finland	2588 inpatients followed up for 2 mo after discharge	Significantly lower risks of rehospitalization with LAIs than oral medications. Clozapine and olanzapine were associated with significantly lower risk of rehospitalization than risperidone.
Tiihonen et al[108], 2017, Sweden	29823 patients followed up for 5.7 yr	Significantly lower risks of rehospitalization and of treatment failure1 with LAIs and clozapine vs no antipsychotic treatment.
Taipale et al[109], 2018, Finland	62250 inpatients followed up for 20 yr	Significantly lower risks of rehospitalization with LAIs and clozapine vs no antipsychotic treatment in first episode and chronic schizophrenia.
Tiihonen et al[77], 2019, Finland	62250 inpatients on antipsychotic monotherapy or antipsychotic combinations followed up for 14 yr	Combination of clozapine and aripiprazole was associated with significantly lower risk of rehospitalization and mortality than clozapine alone in first episode and chronic schizophrenia. Clozapine monotherapy was associated with the most favourable outcomes compared to other antipsychotics.
Luykx et al[82], 2020, Finland	2250 patients on clozapine treatment followed up for more than 1 yr before discontinuation	Compared to no antipsychotic treatment, significantly lower risks of rehospitalization with re-institution of clozapine alone, oral olanzapine, and antipsychotic combinations. Significantly lower risks of treatment failure1with aripiprazole LAI, re-institution of clozapine alone, and oral olanzapine.

¹Treatment failure included re-hospitalization, suicide attempt, treatment discontinuation, medication switch, or death.

LAI: Long-acting antipsychotic injection.

Table 8 Steps for ensuring optimal clozapine treatment[65,81,110,111,120,123,132]

Steps for ensuring optimal clozapine treatment
Adequate assessment	Diagnosis should be established properly. Comorbid conditions should be looked for. Adherence should be determined. Symptoms and other outcome domains should be preferably rated using validated instruments. Caregiver burden and coping should be assessed. Stressors and adverse circumstances should be evaluated.
Proper dosing	Inter-individual and ethnic variability in optimal doses should be considered. If facilities for serum levels are available, doses should be titrated to ensure plasma levels > 350 ng/mL. Doses should be increased slowly with careful monitoring of side effects to reduce the burden of dose-dependent side effects.
Adequate duration	A minimum of 2-3 mo is considered necessary. Durations could be shorter in those with high risk of aggression or self-harm. Durations could be longer in those with negative or cognitive symptoms and in partial responders.
Managing side effects	Many of the common side effects of clozapine can be managed by slow titration, using the least effective dose, reducing doses when side effects develop, adding medications, or adopting lifestyle changes to counter side effects. Additionally, careful monitoring should be carried out for the more serious and idiosyncratic adverse reactions such as agranulocytosis and cardiopulmonary complications.
Managing non-adherence	Careful monitoring of adherence based on multiple sources is necessary. Managing side effects, educating patients to deal with negative attitudes to clozapine, developing a trusting alliance to improve motivation, caregiver education and support to increase their involvement in the patient’s care may help. These measures should ideally be initiated right at the beginning of treatment. Use of long-acting antipsychotic injections may be considered.
Collaboration with patients and caregivers	Both patients and caregivers should be the focus of treatment. Measures should be tailored according to their needs. Goals of treatment should be reduction of symptoms and distress, improving support, forging effective alliances, and promoting patient and caregiver engagement. Simple psychosocial measures including cognitive or behavioural strategies, psychoeducation, and emotional and practical support should be implemented at the start of treatment or as early as possible. More structured interventions can be tried depending on availability of resources and expertise.
Addressing clinician related barriers	Clinicians’ lack of awareness and experience of clozapine treatment and negative attitudes towards clozapine use should be addressed by proper education, dissemination of information, and dedicated facilities.