Antipsychotics

Five^22-26 of the 12 medication meta-analyses reported on antipsychotic augmentation of clozapine exclusively (Table 2). The remaining analyses reviewed augmentation of a variety of agents, including antipsychotics. Barbui et al²² reviewed 21 randomized studies (n = 1480) evaluating chlorpromazine and risperidone as well as agents not available in the United States, such as pipothiazine and sulpiride. The trials consisted of 14 open and 6 double-blind trials. The majority of randomized trials (15/21) were conducted in China. Upon separate analysis, the open trials were found to significantly favor the augmentation group. However, the analysis of the double blind trials revealed no significant difference between placebo and augmenter. Risperidone was the augmenter in 10 trials with 4 of the 10 having a double-blind design. The authors felt there was no support for antipsychotic augmentation of clozapine.

TABLE 2 Pharmacological agents discussed

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Taylor et al²³ evaluated 14 trials consisting of 734 subjects. Augmenters included the second-generation antipsychotics (SGAs) aripiprazole and risperidone and first-generation antipsychotics chlorpromazine, haloperidol, and pimozide as well as agents not available in the United States: amisulpride, sertindole, and sulpiride. Unlike the Barbui et al²² report, this analysis consisted of only randomized, placebo-controlled trials. The results showed a small benefit of the augmenter over placebo, effect size –0.239 (95% confidence interval [CI]: –0.452, −0.026); P = .028. Meta-regression did not find a relationship between treatment duration and symptom reduction. The data do not allow for a recommendation of any particular augmentation agent.

Galling et al²⁴ reviewed augmentation of antipsychotic therapy with a second antipsychotic versus continued monotherapy. Thirty-one studies were reviewed, of which 20 trials (n = 1112) involved clozapine. Augmenters included fluoxetine, pimozide, risperidone, paliperidone, aripiprazole, ziprasidone, sulpiride, and sertindole. Double-blind and higher quality studies found no significant difference between groups.

A recent meta-analysis²⁵ evaluated 12 double-blind randomized clinical trials involving the addition of a SGA to clozapine treatment. Five studies investigated risperidone, and 3 trials investigated aripiprazole. The remaining agents (amisulpride, sertindole, sulpiride, and ziprasidone) had only 1 trial each. Results of the analysis found no significant benefit of augmentation for positive symptoms. A small effect was seen for negative (standardized mean difference [SMD] = –0.38; P = .005; I² = 62.7%) and depressive symptoms (SMD = –0.35; P = .003; I² = 4.9%). The authors²⁵ suggested the statistically significant effects may not be clinically significant. In addition, the quality of evidence for the effect on negative and depressive symptoms was low.

A nationwide cohort study in Sweden was report by Tiihonen et al.²⁶ The study explored the risk of psychiatric rehospitalization in 62 250 patients with schizophrenia during the use of 29 different antipsychotic monotherapy and polypharmacy treatments. The data reported were from April 24 to June 15, 2018. Risks were determined using within-individual analyses to minimize selection bias. The authors reported the lowest risk of psychiatric rehospitalization was found for the combination of clozapine plus aripiprazole (hazard ratio [HR], 0.86; 95% CI: 0.79, 0.94) and was superior to clozapine monotherapy. The risk was lower in the subgroup of patients experiencing their first psychotic break (HR, 0.78; 95% CI: 0.63, 0.96). This population was assumed to be poor responders to monotherapy, but treatment refractory status was not determined. Also, confounding by indication bias could not be ruled out.

Anticonvulsants

Lamotrigine is of interest as an augmenter of clozapine due to its ability to inhibit excess glutamate release.²⁷ Glutamate activity has been put forward as dysfunctional in the pathophysiology of schizophrenia.²⁸ A meta-analysis²⁹ was performed on studies of lamotrigine augmentation of clozapine. Five randomized, placebo-controlled studies were reviewed (Table 2). However, in 3 of the trials,^30,31 the majority of subjects were not receiving clozapine but other SGAs. The 2 studies by Goff et al³⁰ had only 20.6% and 10%, respectively, treated with clozapine. The report by Kremer et al³¹ of study completers (n = 21) had only 1 subject receiving clozapine. The duration of the trials ranged from 10 to 24 weeks, and 161 subjects were included. The primary outcome measure was the PANSS or BPRS total score; the secondary outcome measures consisted of positive and negative symptom ratings. Individually, none of the 5 trials reported a significant difference between lamotrigine and placebo using intent to treat analysis. The results of the meta-analysis found lamotrigine was significantly different from placebo on the primary and secondary outcome variables.

Zheng et al³² evaluated 22 RCTs (n = 1227) published in English and Chinese languages. A variety of anticonvulsants were used, including topiramate (5, n = 270), lamotrigine (8, n = 299), sodium valproate (6, n = 430), and magnesium valproate (3, n = 228). Significant superiority of augmentation was found for studies utilizing topiramate, lamotrigine, and sodium valproate. Topiramate showed significant results for total psychopathology score as well as positive, negative, and general psychopathology symptoms. The all-cause discontinuation for the topiramate trials indicated a high dropout rate (relative risk = 1.99; 95% CI: 1.16, 3.39; P = .01; I² = 0%; number needed to harm [NNH] = 7. Lamotrigine showed marginally significant improvement in total rating scale score. After removal of outliers (2 studies with SMD < –1.0), lamotrigine lost significance. In addition, lamotrigine did not show significant effects for positive, negative, or general psychopathology symptoms. Sodium valproate demonstrated significant reduction in PANSS total score (SMD = –1.26; 95% CI: –2.05, –0.47; P = .002; I² = 91%). The results remained significant with the removal of outliers. The subscales of positive and general psychopathology symptoms showed significant effect, but the negative symptoms demonstrated no change between groups. Study defined response was not different between the valproate-clozapine group and the clozapine-alone group. Lastly, only 3/22 trials included clozapine plasma concentrations to assure the concentration was >350 ng/mL.

Antidepressants and Miscellaneous Agents

Twenty-nine studies evaluating 15 different augmenters were reported by Sommer et al.³³ All were double-blind trials (Table 2). The primary outcome was total symptom severity, and secondary outcomes were subscores for positive and negative symptoms. Sulpiride had significant effects for total, positive, and negative symptoms. Lamotrigine showed significant efficacy for total symptoms; however, the effect disappeared after an outlier was removed. A significant improvement for positive symptoms was found for topiramate; however, similar to lamotrigine, the effect was lost with the removal of an outlier. Citalopram was found to have significant effect for total and negative symptoms. CX516 (a glutamate agonist) showed significant effect on total and negative symptoms. All of the positive results, other than those with lamotrigine, were based on only 1 trial. Mirtazapine and fluoxetine did not show significant changes. The remaining antipsychotics, amisulpride, aripiprazole, haloperidol, and risperidone showed no effect. Of the remaining glutamatergic agents, D-cycloserine, D-serine, glycine, and sarcosine did not show an effect.

Porcelli et al³⁴ evaluated 62 trials (n = 1556). The primary outcome criterion was the mean change in total score on the PANSS or the BPRS. Only 8 RCTs were used for the meta-analysis. These included 5 risperidone studies and 3 lamotrigine trials. The meta-analyses did not support either the use of risperidone or lamotrigine as augmenters of clozapine. Open-label trials of amisulpride, aripiprazole, mirtazapine, and ethyl eicosapentaenoic acid showed evidence for augmentation effects. The ECT augmentation required further evaluation. Tolerability was found to be a problem with risperidone (cognition and glucose control, hyperprolactinemia, extrapyramidal symptoms, and weight gain) and amisulpride (bradykinesia, akathisia, tremor, and increased prolactin serum concentrations).

Correll et al³⁵ conducted a systematic review of meta-analyses of pharmacologic treatment strategies added to antipsychotic drug treatments and compared these to antipsychotic monotherapy. Clozapine combinations were compared separately. The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms. There were 5 strategies that augmented clozapine (antidepressants, antipsychotics, glycine, lamotrigine, topiramate). None of the combination strategies evaluating total psychopathology with clozapine outperformed controls. The authors also reported, when considering the quality of the studies in the meta-analysis, the effect sizes were inversely correlated with study quality. The authors concluded that patients not responding to clozapine are unlikely to have a response to an augmentation treatment.

Siskind et al³⁶ reviewed 46 studies, 16 from a Chinese database, consisting of 25 interventions. Outcome criteria included total psychosis symptom scores, PANSS and BPRS, negative symptoms (Scale for the Assessment of Negative Symptoms and PANSS negative symptom subscale and positive symptoms Scale for the Assessment of Positive Symptoms). Studies consisted of RCTs with clozapine plus augmenter versus placebo or another augmenter. Interventions included antipsychotics (aripiprazole, risperidone, sulpiride/amisulpride, sertindole, haloperidol, penfluridol, olanzapine, pimozide quetiapine, and ziprasidone), antidepressants (fluoxetine, paroxetine, duloxetine, and mirtazapine), and mood stabilizers (sodium valproate, topiramate, lamotrigine, and lithium). Other pharmacologic agents consisted of memantine, glycine, sarcosine, minocycline, and ginkgo biloba. Nonpharmacologic interventions included cognitive behavioral therapy, ECT, and transcranial magnetic stimulation. Four interventions showed significant response: aripiprazole, fluoxetine, and sodium valproate for total symptom reduction and memantine for negative symptoms. However, when only high-quality studies and studies that used rating scales were analyzed, aripiprazole lost significance of all psychosis outcomes. Fluoxetine had 1 high-quality study and 5 low-quality studies. The exclusion of the low-quality studies resulted in the loss of significance for positive and negative symptoms.

Electroconvulsive Therapy

Three recent meta-analyses^37-39 were performed to determine the effect of ECT as an augmenter in clozapine-resistant patients (Table 2). In addition, there are many literature reviews and case series that explore this question that are not reviewed here. Response definitions ranged from 25% to 50% reduction in total PANSS or BPRS and remission is defined as ≥75% reduction in total PANSS or BPRS in the studies.

Lally et al³⁷ reviewed five trials (n = 71), 4 of which were open trials. Response was defined as a >40% reduction in BPRS scores. They found the proportion of subjects who responded was 54% (95% CI: 21.8%, 83.6%) for all 5 trials. The response rate in open-label trials (n = 32) was 56% (95% CI: 19.4%, 87.2%), and in the RCT (n = 39), it was 48.7% (95% CI: 33.6%, 64.0%).

Ahmed et al³⁸ reviewed 23 studies (n = 1179) comparing ECT augmentation of clozapine versus ECT augmentation of other antipsychotics. The outcome criteria was total psychopathology measured by the PANSS or BPRS. The ECT-clozapine group had an SMD = 1.504, and the ECT-other antipsychotic group had an SMD = 0.891. The authors speculated there may be a synergistic effect of ECT with clozapine versus other antipsychotics.

Wang et al³⁹ reported on 18 RCTs (n = 1769) evaluating ECT augmentation of clozapine treatment. Seventeen studies were published in China and 1 in the United States. Prior meta-analyses have not included studies published in Chinese as they were not accessible until now. Post-ECT and end-point assessments revealed a significant improvement in symptoms. Response was associate with a number needed to treat [NNT] = 4 and remission had an NNT = 14. Subject-reported adverse events included memory impairment (NNH = 4) and headache (NNH = 8). This study represents the largest meta-analysis to date of ECT augmentation of clozapine treatment.

Significant improvement was evident 1 to 2 weeks after the initiation of the ECT treatments. A sensitivity analysis indicated that the improvement was not driven by outlier studies. Overall, ECT augmentation of clozapine was generally safe and well tolerated.

Individual Studies

There are several agents that have additional data that warrants discussion regarding use in ultra-TRS patients.

Part 1

Patient AB developed schizophrenia at approximately age 20 and is now age 50.

AB experienced persistent auditory hallucinations, which took the form of voices making comments about him. The content of the hallucinations revolved around negative themes, such as “you will be alone when mother dies,” “no one will help you,” “you shouldn't be in your apartment.” In addition, AB presents with negative symptoms involving lack of motivation to carry out tasks, little interest in any activities, and isolation in the apartment. The patient is obese with a weight of 300 lbs. AB smokes and gets little, if any, exercise.

AB had been treated with a variety of antipsychotics over the years with little effect. Most of the trials had adequate dose and duration.

AB met criteria for a clozapine trial in that he fulfilled the criteria for treatment refractory schizophrenia of at least 2 trials of antipsychotic treatments at appropriate doses and duration. Clozapine was titrated to 300 mg/d. Additional medication included bupropion extended release 300 mg at bedtime and topiramate 50 mg at bedtime to reduce appetite. The clozapine trough plasma concentration was drawn at steady state and was found to be 318 ng/mL.

Part 2

Due to persistent symptoms, the clozapine dose was gradually increased to 700 mg/d over 15 months, ultimately achieving a clozapine plasma concentration = 828 ng/mL and norclozapine = 444 ng/mL. Over this period, the patient's symptoms improved with a reduction in paranoia and auditory hallucinations. AB continued to report low motivation and low energy.

Bupropion extended release was tapered and discontinued due to unclear indication, potential seizure risk, and potential stimulation of positive symptoms. No emergence of depressive symptoms occurred. AB's mother reported the clozapine has been quite helpful with the paranoia and voices over the past 6 months. AB still suffers from amotivation, does not leave the apartment, and does not get any exercise.

Part 3

In light of the persistence of negative symptoms, AB's case was reviewed to determine if an augmentation strategy would be indicated. Applying the 5Cs assessment, the diagnosis was verified as schizophrenia; no comorbid depression was found. AB was compliant with medication. Clozapine plasma concentrations were found to be above the therapeutic threshold. AB had positive support from the mother and did not have any other stressors present. Target symptoms were identified to include amotivation, lack of interest in activities, and isolating in the apartment. A review of the literature investigating treatments for negative symptoms was conducted. Memantine studies indicated effects in treating negative symptoms with good tolerability. The report of 52-week data showing improvement in cognition and psychopathology supported the use of memantine.⁴⁷ The plan was discussed with AB and the mother. They were accepting of the plan. Memantine was initiated at 10 mg/d for 1 week, then increased to 20 mg/d.

Part 4

One month later, AB presented with stable symptoms and a low occurrence of voices. At the 2-month visit, AB reported interest in doing some art projects, which used to be a preferred activity in the past. At the 3-month visit, AB described going to the apartment's exercise room riding the stationary bike on 3 occasions.

Although these changes appear quite minimal, for this patient, they represent a potential beginning of improvement in negative symptoms. The data available suggest continued improvement over 52 weeks. For these gains to be viewed as successful, the improvement will have to continue and expand over the next 9 months.