key: cord-0067248-uowssh33 authors: Chakrabarti, Subho title: Clozapine resistant schizophrenia: Newer avenues of management date: 2021-08-19 journal: World J Psychiatry DOI: 10.5498/wjp.v11.i8.429 sha: f3a77bb86ad8229ce68f45da8290388eeac8f407 doc_id: 67248 cord_uid: uowssh33 About 40%-70% of the patients with treatment-resistant schizophrenia have a poor response to adequate treatment with clozapine. The impact of clozapine-resistant schizophrenia (CRS) is even greater than that of treatment resistance in terms of severe and persistent symptoms, relapses and hospitalizations, poorer quality of life, and healthcare costs. Such serious consequences often compel clinicians to try different augmentation strategies to enhance the inadequate clozapine response in CRS. Unfortunately, a large body of evidence has shown that antipsychotics, antidepressants, mood stabilizers, electroconvulsive therapy, and cognitive-behavioural therapy are mostly ineffective in augmenting clozapine response. When beneficial effects of augmentation have been found, they are usually small and of doubtful clinical significance or based on low-quality evidence. Therefore, newer treatment approaches that go beyond the evidence are needed. The options proposed include developing a clinical consensus about the augmentation strategies that are most likely to be effective and using them sequentially in patients with CRS. Secondly, newer approaches such as augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could be considered. Lastly, perhaps the most effective way to deal with CRS would be to optimize clozapine treatment, which might prevent clozapine resistance from developing. Personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use are the principal ways of ensuring optimal clozapine treatment. At present, these three options could the best way to manage CRS until research provides more firm directions about the effective options for augmenting clozapine response. Although antipsychotic treatment is one of the principal options for the management of schizophrenia, about a third of the patients with schizophrenia do not respond well to first-or second-generation antipsychotics [1, 2] . People with treatment-resistant schizophrenia (TRS) continue to have psychotic symptoms and functional impairment despite adequate antipsychotic use. TRS is associated with greater severity of symptoms, more frequent relapses, repeated hospitalizations, poorer socio-occupational functioning, and poorer quality of life(QOL). Consequently, it imposes a substantial economic and social burden on patients, families, and healthcare services [1, 3] . Despite some contrary opinions, there is a widespread consensus that clozapine is the treatment of choice for patients with TRS [4, 5] . However, even with optimal clozapine treatment, 40%-70% of the patients with TRS do not benefit from monotherapy with clozapine[6-9]. Patients with clozapine-resistant schizophrenia (CRS) are probably among the most severely ill of all patients with this disorder. A study comparing TRS and CRS found that the overall severity of the illness and positive and negative symptoms were significantly higher, while the QOL score was significantly lower among patients with CRS[10] Moreover, symptom severity among patients with CRS did not improve much over 6 mo of follow-up. Other estimates have suggested that apart from the greater symptom severity, patients with CRS are likely to be more frequent users of healthcare services and more likely to have multiple and prolonged hospitalizations [11] . Consequently, the cost of their care and the adverse impact of CRS on patients and their caregivers is also likely to be substantially greater than TRS [7, 12] . Such serious consequences of CRS often compel clinicians to try new and different strategies to treat these patients. The option most commonly adopted is to add another psychotropic agent to clozapine to enhance its effects [9, 11] . However, the evidence to date indicates that augmentation with medications or other treatments yields little or no additional benefits for these patients [13] . The treatment of CRS thus continues to pose a formidable challenge for clinicians. Moreover, the size of this group of patients will increase as the use of clozapine for TRS increases. Therefore, newer ways of managing CRS have to be explored. Accordingly, this review attempts to briefly summarize the research in this area, followed by a discussion of certain treatment options and strategies that appear promising. CRS have not utilized such definitions. Moreover, a major criticism of the current constructs of CRS is that they rely excessively on positive symptoms of schizophrenia [11, 17, 18] . Other domains such as negative, cognitive, or depressive symptoms, or QOL have not received sufficient attention. This gives rise to substantial heterogeneity in the CRS groups selected using such definitions, which further hinders research. Although measures such as more precise delineation of target symptoms and differentiating between "minimum and optimal criteria" required for CRS In routine clinical practice, the commonest strategy to deal with CRS is augmentation with another antipsychotic[9,11,20,21]. Mood stabilizer or antidepressant augmentation is used less frequently. Some treatment guidelines also endorse augmentation with antipsychotics [13] . Over the past 25 years, many trials of clozapine augmentation with medications and other treatments have been conducted. Additionally, more than 50 reviews on the subject including narrative and systematic reviews, individual metaanalyses, and reviews of different meta-analyses have been published. been examined less frequently. A similar inconsistency is apparent with some metaanalyses showing modest benefits, while others report no effects on these symptoms. No benefit of antidepressant augmentation on reduction in overall, positive, and negative symptom severity. Methodological lacunae: One of the principal reasons for the inability to find effective medication augmentation options for CRS is the methodological shortcomings of current research. Even in the better quality RCTs, there is considerable heterogeneity in terms of the definitions used, the types and numbers of patients included, the duration of trials, and the outcomes examined. The methodological lacunae of the RCTs have in turn affected the methodological quality of meta-analytic examinations of the evidence. For example, in a systematic review of 21 meta-analyses only one was judged to have "very little risk of bias;" 7 had "low risk of bias," and the rest had "high risk of bias"[2]. Therefore, there is considerable uncertainty even about the findings of meta-analytic studies. Some of the more recent reviews have concluded that electroconvulsive therapy (ECT) is an effective augmentation strategy, especially when medications fail to decrease persistent positive symptoms[2,8,20,46,51]. However, this conclusion appears to be based on a single meta-analysis of 18 RCTs [52] , which showed that the ECT-clozapine combination was better than clozapine alone in reducing positive symptoms. Then again, 17 of these RCTs were conducted in China and are not easily accessible [53] . As shown in Table 4 , there are only two small RCTs of ECT augmentation of clozapine response. The first showed that the clozapine-ECT combination was more effective than clozapine alone in TRS[54], whereas the second did not find the combination to be more effective in CRS [55] . The rest of the evidence consists of non-randomized trials[56] and case studies. Thus, the higher response rates of the clozapine-ECT combination reported in systematic reviews[57-61] and other meta-analyses[62-64] are largely based on low-quality evidence, obtained mainly among patients with TRS, and Two systematic reviews of psychosocial interventions have concluded that CBT can be effective among patients with poor response to clozapine[33,68]. As shown in Table 5 , the evidence-base for CBT until recently had consisted of a few trials with small . This was the largest trial among all RCTs of clozapine augmentation. It employed standardized definitions of CRS and trained therapists who administered manual-based CBT to patients from routine clinical settings. After 9 mo of active treatment, the total Positive and Negative Symptom Scale scores, positive symptoms, emotional distress, and excitement had reduced significantly in the CBT group compared to the usual treatment group. However, at the end of 21 mo, there were no significant differences in the Positive and Negative Symptom Scale scores between the two groups, leading to the conclusion that CBT augmentation was not effective in CRS. Nevertheless, other indices suggested that CBT might be useful for a proportion of patients, and patients' ratings of recovery were greater in the CBT group at 21 mo. Other noteworthy advantages of CBT were the high adherence rates, negligible adverse effects, high acceptability, and effect sizes comparable to medication augmentation. Therefore, others have interpreted these results differently to emphasize the positive effects of CBT augmentation[2,66,76]. Moreover, it has been pointed out that the persistence of positive effects beyond the active treatment period is not the best indicator of the efficacy of CBT [76] . Thus, if the standards for medication trials were to be applied to this RCT, the conclusion would be that CBT was an effective augmentation strategy for CRS after 9 mo of treatment. This brief update of the existing literature shows that augmentation of clozapine response in CRS with medications, ECT, or CBT is largely ineffective. Any favourable outcome for augmentation is usually based on low-quality or limited evidence, and the clinical significance of the small effects obtained in some meta-analyses is unclear. Moreover, because of the inconsistent results and methodological uncertainties, the August 19, 2021 Volume 11 Issue 8 evidence offers no definite conclusions about the most effective augmentation strategies. Nevertheless, it has been suggested that the lack of evidence should not discourage clinicians from trying out these strategies in individual patients. This advice appears to be based on two assumptions. First, the lack of significant benefits applies only to entire groups of patients being evaluated in RCTs, whereas there may be considerable variability in individual responses of the patients comprising these groups[18,25,29,40]. Thus, there is a possibility that some patients may benefit from augmentation, though at present there is no way to identify these potential responders. Moreover, given the widespread adverse impact of CRS, even modest benefits are considered acceptable in clinical settings [7, 22, 46] . Therefore, the sequential use of different augmentation strategies is considered to be a realistic option in clinical practice. To reduce the disparity between the evidence-based findings and clinical practice, researchers have been increasingly relying on clinical consensus to guide the management of complex and burdensome conditions such as CRS. A recent effort on these lines arrived at the following recommendations for augmentation of clozapine nonresponse: personalizing doses to reach plasma levels ≥ 350 ng/mL; a 3 mo trial for patients with positive symptoms; shorter treatment trials for those with violence or self-harm (2 mo) and longer periods (4 mo) for patients with negative or cognitive symptoms [13] . For persistent positive symptoms, adding aripiprazole, amisulpride, or ECT was suggested. Augmentation with antidepressants was recommended for negative symptoms while adding antidepressants, antipsychotics, mood stabilizers, or ECT to clozapine was proposed for CRS with increased risks of aggression or selfharm. Lastly, CBT or other psychosocial interventions were also felt to be useful. It was apparent that these clinicians were going beyond the current evidence while making some of these recommendations. For example, though there is little support in the literature for augmentation of clozapine with a second antipsychotic, low-quality evidence or single RCTs have suggested that risperidone, aripiprazole, and amisulpride may be beneficial ( Table 2) . The group also relied on naturalistic studies showing that the clozapine-aripiprazole combination may have positive effects [77] . Similarly, for recommendations about antidepressants, positive evidence for antidepressant augmentation in schizophrenia was cited[78,79], though the evidence for similar effects of antidepressant augmentation in CRS is limited (Table 3) . Augmentation with mood stabilizers and ECT was recommended despite the acknowledgement that the evidence for these strategies is insufficient (Tables 3 and 4) . The recommendation for using CBT if other treatments failed was based on the recent CBT trial [75] , which concluded that certain individuals with CRS may benefit from a practical trial of CBT augmentation. Clozapine augmentation was preferred over a switch to a different antipsychotic because of the consistent evidence of adverse outcomes following cessation of clozapine[8,11,80-82]. Switching to high-dose olanzapine has been suggested as an alternative, but this option is not supported by evidence [81, 83] . Finally, though most of the evidence indicates that these augmentation strategies are safe and well-tolerated[22,25,26,29], the possibility of new side effects arising during combined treatment could not be discounted[9,12,18,28,32]. Therefore, cautious monitoring of all patients for the duration of the augmentation trial was also recommended. Augmentation with long-acting antipsychotic injections: Apart from problems of resistance, non-adherence is a major hindrance to effective treatment with clozapine. Although non-adherence with clozapine may be lower than other antipsychotics, rates of intentional non-adherence vary from 23%-55% during treatment[84-88]. In such situations initiating a long-acting antipsychotic injection (LAI) remains the only option [89] . Intramuscular clozapine appears to have some benefits in enhancing adherence, but it has not been used frequently [90, 91] . Recent studies suggest that apart from reducing non-adherence, LAI augmentation of clozapine may also have a role in enhancing clozapine response in CRS. As shown in Table 6 , this evidence is still preliminary and consists mostly of series of patients and observational studies[92-102]. However, mirror-image studies that are considered the current standard for evaluating LAI efficacy [103, 104] have also been conducted. Taken together, this body of evidence suggests that the combination of clozapine with LAIs leads to a reduction in all types of symptoms and behavioural problems such as aggression and suicidality as well as improvements in social functioning. The lowered risk of relapses and reduction in the number and length of hospitalizations has also been replicated consistently. Lastly, it appears that lower doses of both medications are required, while side effects are either less, or no more common with the combination than with clozapine monotherapy. Indirect evidence for the effectiveness of clozapine-LAI combinations also comes from several Scandinavian nationwide cohort studies of antipsychotic treatment summarized in Table 7 [77,82, [105] [106] [107] [108] [109] . These provide the strongest support for the notion that clozapine and LAIs are the two most effective treatments for patients with both first episode and chronic schizophrenia. Incidentally, some of these studies have also shown that the combination of clozapine and aripiprazole is more effective than clozapine monotherapy [77] . Therefore, the combination of clozapine and LAIs appears to be a promising option that needs to be examined further for its usefulness in the management of CRS. A re-evaluation of psychosocial augmentation strategies: Although the evidence reviewed in Table 5 suggests that augmentation with CBT does not yield consistent benefits in CRS, there are several reasons to re-examine the usefulness of psychosocial augmentation strategies. To begin with, CBT augmentation appears to be effective for persistent positive symptoms in TRS[20,68,75,76]. Moreover, the largest and most meticulously conducted CBT trial has shown a small but significant benefit for patients with CRS following the active intervention phase[66,75,76]. The same trial has suggested that CBT is one of the safest and acceptable augmentation options for patients with CRS. The evidence from this study and other trials shows that CBT augmentation has added benefits such as improvements in socio-occupational functioning and QOL. Moreover, symptomatic remission appears to be faster with CBT augmentation, and the benefits obtained may persist longer[71,72,74]. CBT augmentation early in the course of clozapine treatment may further enhance its benefits[68-70,74]. 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 failure 1 with LAIs and clozapine vs no antipsychotic treatment. Taipale et al [109] , 2018, 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 reinstitution of clozapine alone, oral olanzapine, and antipsychotic combinations. Significantly lower risks of treatment failure1with aripiprazole LAI, re-institution of clozapine alone, and oral olanzapine. 1 Treatment failure included re-hospitalization, suicide attempt, treatment discontinuation, medication switch, or death. LAI: Long-acting antipsychotic injection. Further, it has been proposed that rather than using only CBT, multi-component psychosocial interventions using different techniques might be more effective in enhancing clozapine response[33, 110, 111] . Though CBT is the most common psychosocial treatment used in patients with TRS, there is evidence to suggest that other types of interventions might be equally effective [68, 112] . Psychoeducation and family interventions are also effective for schizophrenia [113] , but they have not been tried out as augmenting strategies in TRS or CRS [20, 68] . Lastly, psychosocial aug-mentation might be useful in other ways, for example in improving adherence to clozapine. An RCT that compared CBT with psychoeducation among patients with TRS on clozapine showed that both treatments led to improvements in patient empowerment, treatment alliance, and medication persistence [114] . Thus, while there may be no compelling evidence in favour of psychosocial augmentation strategies in CRS, there is scope for further evaluation of these potentially useful treatments. The relative ineffectiveness of the different augmentation strategies suggests that a more fruitful option could be to try and prevent resistance to clozapine treatment from developing. Predicting who among patients with TRS will not respond adequately to clozapine may be helpful because augmentation strategies could be instituted early in such patients to mitigate the adverse effects of clozapine resistance. However, despite over 300 studies of prediction of clozapine response, consistent predictors of response have not been found. Some reviews have concluded that there are no reliable predictors of clozapine response because of the inconsistent results and methodological uncertainties of existing research [115, 116] . On the other hand, an older systematic review and a more recent meta-analysis have found that older age, greater severity of symptoms, especially negative symptom severity, poorer functioning, and non-paranoid subtypes could predict clozapine non-response [117, 118] . Low cerebrospinal homovanillicacid to 5-hydroxyindoleacetic acid ratios and normal structure and August 19, 2021 Volume 11 Issue 8 function of the prefrontal cortex have also emerged as reliable predictors of good response in some studies [117, 119] . Consequently, because of the inconclusive nature of this evidence, currently the only way to predict clozapine resistance is to carry out an adequate trial of clozapine treatment under optimal conditions [20, 115] . Ensuring adequate treatment with clozapine may thus be the best option to prevent clozapine resistance. The necessary steps for optimizing clozapine treatment are listed in Table 8 . Personalized dosing is a key component because of the wide variations in dose-blood level ratios between individuals and because many patients respond at lower doses [120, 121] . Data on gender differences in clozapine treatment are scarce, and results are often inconsistent [122] . This is particularly true for response to clozapine treatment. Though the response is usually poorer in women [116, 117, 122] , research on clozapine's effectiveness has also found better outcomes among women, although these differences in their favour are often of doubtful clinical significance [115, 117, 123] . Others have found no differences in outcome between the two genders [118] . In contrast, differences in pharmacokinetics are reported more consistently [122, 124, 125] . Women have lower renal clearance of clozapine than men because of differences in the activity of cytochrome P450 enzymes such as CYP1A2. Most studies have found higher plasma levels of clozapine in women, and some have also found higher levels of its metabolite norclozapine. Higher dose-blood level ratios have also been found in women. Therefore, women usually require lower doses of clozapine [124] . These pharmacokinetic differences also increase the risk of dose-dependent side effects in women, particularly metabolic side effects [122, 126] . Accordingly, most of the evidence on gender differences in side effects of clozapine relates to metabolic disturbances [122] . However, findings are not consistent, and both genders appear to have increased risk of metabolic syndrome in different reports [122, [126] [127] [128] . Hypertension, elevated triglycerides, lower high-density lipoprotein levels, and cardiac abnormalities appear to be more common in men [122] . Women are more likely to develop hyperglycaemia and diabetes and increases in weight and body mass index [122, 126] . There is very little evidence of gender differences in other side effects, though certain studies have found haematological abnormalities and constipation to be commoner among women [122, 125, 128, 129] . Unlike the influence of gender, ethnicity does not appear to have any impact on treatment response obtained with clozapine [115, 130] . On the other hand, there are ethnic differences in pharmacokinetic profiles of clozapine [122] . More specifically, several studies among Asian patients have consistently indicated that they require about half the standard dose of clozapine due to their lowered clozapine metabolism [131] [132] [133] [134] [135] . The dose of clozapine required for adequate response among Asians varies from 150mg/d among women to 300 mg/d for men who smoke. Therefore, Asian patients need lower doses at the start of treatment and slower upward titration to reach their optimum dose. Despite these pharmacokinetic dissimilarities, ethnic differences seem to have minimal impact on the prevalence of adverse effects of clozapine [129] . Nevertheless, non-White ethnicity is a risk factor for metabolic syndrome, and certain studies have found a higher prevalence of hypertension and weight gain in Asians [127, 136] . Others have found a higher risk of agranulocytosis in Asian patients [137] . This again emphasizes the fact that the best way to individualize clozapine doses is to base them on blood levels. Doing so has the added advantages of lessening side effects and allowing adherence to be monitored. However, facilities for blood levels are not always available. Standardized dosing schedules could be used in such instances [132] . Many of the side effects encountered with clozapine are dose-dependent including sedation, tachycardia, hypersalivation, enuresis, constipation, delirium, obsessivecompulsive symptoms, seizures, and orthostatic hypotension[81,120,138] Among all antipsychotics, the prevalence of metabolic dysfunction or metabolic syndrome is the highest for clozapine and olanzapine [81, 126, 127, 132, 139] . Whether metabolic side effects are also dose-dependent is not clear [81, 138] . However, systematic reviews and meta-analyses have indicated a dose-outcome association between clozapine and metabolic side effects, particularly with lipid levels and weight gain [140, 141] . Risk factors for metabolic syndrome include higher baseline weight or body mass index, gender, non-White, possibly Asian ethnicity, and several genetic and peptide markers [126, 127, 136, 139, 142] . Somewhat paradoxically, metabolic disturbances are also associated with a reduction in symptoms [126, 127] . 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. 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. 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. 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. 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. 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. Optimizing clozapine doses is the principal way of managing most dose-dependent side effects. Using the lowest effective dose, slow increase in doses, and dose adjustments to minimize side effects is always recommended [81, 120, 123] . Discontinuation of concomitant medications that might not be essential also reduces the side effect burden [120] . Only serious and life-threatening adverse reactions such as agranulocytosis and some cardiopulmonary complications require abrupt discontinuation of clozapine [81, 120] . Some side effects such as neuroleptic malignant syndrome, thromboembolism, or diabetic ketoacidosis may require temporary discontinuation followed by re-initiation of clozapine [81] . In most other situations, the dose of clozapine should be reduced very gradually to avoid worsening of clinical state or emergence of withdrawal symptoms[120]. When side effects persist despite optimizing the dose of clozapine, the options include adding other medications, instituting non-pharmacological measures to manage side effects, or combining clozapine with another antipsychotic [120, 138] . In the case of metabolic syndrome, adequate treatment of risk factors and metabolic derangements is essential [143] . Meta-analyses of interventions for metabolic side effects have shown that adjunctive metformin is the most effective strategy [144, 145] . Behavioural weight management strategies are also recommended though the evidence for their efficacy is uncertain [120, 138, 144] . Adding aripiprazole to clozapine to reduce both the clozapine dose and metabolic disturbances has also been suggested, but the evidence for this option is limited [120, 144] . Minimizing the side effect burden is necessary because about 40% of the patients (range 21%-67%) stop taking clozapine in the first few years of treatment [82, 84, 86, 87, 146] . In 20%-30% of them, discontinuation is because of intolerable side effects, though intentional non-adherence appears to be somewhat more common [84, 85, 87, 88, 147] . Managing non-adherence requires open and non-judgmental discussions about medication-taking with patients, monitoring of adherence based on all available methods including caregiver reports, education to deal with misconceptions about treatment, and building trusting alliances with patients and families to ensure continued treatment. A collaboration with the patient and the family is an essential part of optimizing clozapine treatment that is often overlooked [65, 110, 111, 120] . Shared decision-making about treatment, education, stress-management, support, and involvement of caregivers are ways of ensuring truly collaborative alliances. Lastly, increasing evidence indicates substantial underutilization and delayed use of clozapine [148, 149] . 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