To synthesize the information relevant for clinical practice on clozapine-antidepressant co-prescription concerning pharmacokinetic drug-drug interactions (DDI), adverse drug reactions (ADRs) associated with the co-prescription, antidepressant add-on for clozapine-resistant symptoms and antidepressant add-on for clozapine-induced ADRs.

Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through April 2023. Data were synthesized narratively.

ADRs are most often induced by the co-prescription of antidepressants that inhibit CYP enzymes (fluvoxamine, fluoxetine, paroxetine). Fluvoxamine add-on is hazardous because of its potent inhibition of clozapine metabolism and has few indications (lowering daily number of clozapine tablets, reducing norclozapine-induced metabolic disturbances and other dose-dependent clozapine-induced ADRs). ADR frequency may be reduced by therapeutic drug monitoring and knowledge of other factors impacting clozapine metabolism (pneumonia, inflammation, smoking, etc.). Improvement of negative symptoms is the most documented beneficial effect of antidepressant add-on for clozapine-resistant psychotic symptoms. The add-on antidepressant should be chosen according to its safety profile regarding DDI with clozapine: antidepressants inhibiting clozapine metabolism or increasing the anticholinergic load should be avoided. Other indications of antidepressant add-on (affective or obsessive compulsive symptoms, sialorrhea, and enuresis) are poorly documented.

Antidepressant add-on to clozapine is associated with potential benefits in clozapine users as this strategy may contribute to reduce the burden of clozapine-resistant symptoms or of clozapine-induced ADRs. Further studies are needed to determine whether antidepressant add-on can reduce the risk of clozapine discontinuation.

The augmentation of clozapine with electroconvulsive therapy (ECT) has been an optimal treatment option for patients with treatment- or clozapine-resistant schizophrenia. Using data from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics survey, which was the largest international psychiatry research collaboration in Asia, our study aimed to develop a machine learning algorithm-based substantial prediction model for the augmented use of clozapine with ECT in patients with schizophrenia in terms of precision medicine. A random forest model and least absolute shrinkage and selection operator (LASSO) model were used to develop a substantial prediction model for the augmented use of clozapine with ECT. Among the 3744 Asian patients with schizophrenia, those treated with a combination of clozapine and ECT were characterized by significantly greater proportions of females and inpatients, a longer duration of illness, and a greater prevalence of negative symptoms and social or occupational dysfunction than those not treated. In the random forest model, the area under the curve (AUC), which was the most preferred indicator of the prediction model, was 0.774. The overall accuracy was 0.817 (95% confidence interval, 0.793−0.839). Inpatient status was the most important variable in the substantial prediction model, followed by BMI, age, social or occupational dysfunction, persistent symptoms, illness duration > 20 years, and others. Furthermore, the AUC and overall accuracy of the LASSO model were 0.831 and 0.644 (95% CI, 0.615−0.672), respectively. Despite the subtle differences in both AUC and overall accuracy of the random forest model and LASSO model, the important variables were commonly shared by the two models. Using the machine learning algorithm, our findings allow the development of a substantial prediction model for the augmented use of clozapine with ECT in Asian patients with schizophrenia. This substantial prediction model can support further studies to develop a substantial prediction model for the augmented use of clozapine with ECT in patients with schizophrenia in a strict epidemiological context.

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.

Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine.

Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS.

26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group.

In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Treatment options for clozapine resistance are diverse whereas, in contrast, the evidence for augmentation or combination strategies is sparse.

We aimed to extract levels of evidence from available data and extrapolate recommendations for clinical practice.

We conducted a systematic literature search in the PubMed/MEDLINE database and in the Cochrane database. Included meta-analyses were assessed using Scottish Intercollegiate Guidelines Network criteria, with symptom improvement as the endpoint, in order to develop a recommendation grade for each clinical strategy identified.

Our search identified 21 meta-analyses of clozapine combination or augmentation strategies. No strategies met Grade A criteria. Strategies meeting Grade B included combinations with first- or second-generation antipsychotics, augmentation with electroconvulsive therapy for persistent positive symptoms, and combination with certain antidepressants (fluoxetine, duloxetine, citalopram) for persistent negative symptoms. Augmentation strategies with mood-stabilisers, anticonvulsants, glutamatergics, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or cognitive behavioural therapy met Grades C-D criteria only.

More high-quality clinical trials are needed to evaluate the efficacy of add-on treatments for symptom improvement in patients with clozapine resistance. Applying definitions of clozapine resistance would improve the reporting of future clinical trials. Augmentation with second-generation antipsychotics and first-generation antipsychotics can be beneficial, but the supporting evidence is from low-quality studies. Electroconvulsive therapy may be effective for clozapine-resistant positive symptoms.

A fair amount of subjects with schizophrenia do not respond to clozapine and are defined 'ultra-resistant'. In this systematic review and meta-analysis, we tested the efficacy of adjunctive second-generation antipsychotics (SGAs) for main symptom domains (positive, negative, and depressive symptoms) in individuals with clozapine-resistant schizophrenia. We searched main electronic databases till December 2017. We included twelve double-blind, randomized, placebo-controlled trials (RCTs), evaluating the efficacy of SGAs for clozapine non/partial responders. We did not find any difference between SGAs and placebo (standardized mean difference, SMD = -0.21; p = 0.170; I² = 68.0%) in improving positive symptoms. The effect size varied according to RCT duration (p = 0.025) and assessment methods (p = 0.016). Low-moderate effects of SGAs on both negative (SMD = -0.38; p = 0.005; I² = 62.7%) and depressive symptoms (SMD = -0.35; p = 0.003; I² = 4.9%), were estimated. In sum, our meta-analysis highlights the lack of efficacy of SGAs as add-on treatment for positive symptoms in clozapine-resistant schizophrenia. A small benefit of SGAs was estimated for both negative and depressive symptoms. Further RCTs are needed to establish efficacy and tolerability of SGAs or other augmentation strategies for different symptoms of clozapine-resistant schizophrenia.

Treatment-resistant schizophrenia (TRS) is common and debilitating. A subgroup of patients even has clozapine-resistant schizophrenia (CRS). We aimed to evaluate the efficacy and safety of electroconvulsive therapy (ECT) augmentation of clozapine for CRS. Systematic literature search of randomized controlled trials (RCTs) reporting on ECT augmentation of clozapine in CRS. Co-primary outcomes included symptomatic improvement at post-ECT assessment and study endpoint. Eighteen RCTs (n = 1769) with 20 active treatment arms were identified and meta-analyzed. Adjunctive ECT was superior to clozapine regarding symptomatic improvement at post-ECT assessment (Standardized Mean Difference (SMD) = -0.88, 95% Confidence Interval (CI): -1.33 to -0.44; I² = 86%, P = 0.0001) and endpoint assessment (SMD: -1.44, 95%CI: -2.05 to -0.84; I² = 95%, P < 0.00001), separating as early as week 1-2 (SMD = -0.54, 95%CI: -0.88 to -0.20; I² = 77%, P = 0.002). Adjunctive ECT was also superior regarding study-defined response at post-ECT assessment (53.6% vs. 25.4%, Risk Ratio (RR) = 1.94, 95%CI: 1.59-2.36; I² = 0%, P < 0.00001, number-needed-to-treat (NNT) = 3, 95%CI: 3-5) and endpoint assessment (67.7% vs. 41.4%, RR = 1.66, 95%CI: 1.38-1.99; I² = 47%, P < 0.00001, NNT = 4, 95%CI: 3-8), and remission at post-ECT assessment (13.3% vs. 3.7%, RR = 3.28, 95%CI: 1.80-5.99; I² = 0%, P = 0.0001, NNT = 13, 95%CI: 6-100) and endpoint assessment (23.6% vs. 13.3%, RR = 1.80, 95%CI: 1.39 to 2.35; I² = 5%, P < 0.0001, NNT = 14, 95%CI: 6-50). Patient-reported memory impairment (24.2% vs. 0%; RR = 16.10 (95%CI: 4.53-57.26); I² = 0%, P < 0.0001, number-needed-to-harm (NNH) = 4, 95%CI: 2-14) and headache (14.5% vs 1.6%; RR = 4.03 (95%CI: 1.54-10.56); I² = 0%, P = 0.005, NNH = 8, 95%CI: 4-50) occurred more frequently with adjunctive ECT. No significant group differences were found regarding discontinuation and other adverse effects. Despite increased frequency of self-reported memory impairment and headache, ECT augmentation of clozapine is a highly effective and relatively safe treatment for CRS.

CRD42018089959.

Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies.

We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses.

On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing.

To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia.

Systematic search of PubMed and PsycInfo until May 13, 2016.

Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia.

Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine.

The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities.

Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, -1.27 [95% CI, -2.35 to -0.19] to -0.23 [95% CI, -0.44 to -0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001), yet effect sizes were inversely correlated with study quality (correlation coefficient, -0.06; 95% CI, 0.01 to -0.12; P = .02).

Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature.

The specific efficacy of antipsychotics on negative symptoms is questionable, suggesting an urgent need for specific treatments for negative symptoms. This review includes studies published since 2014 with a primary or secondary focus on treating negative symptoms in schizophrenia. Special emphasis is given to recently published meta-analyses. Topics include novel pharmacological approaches, including glutamatergic-based and nicotinic-acetylcholinergic treatments, treatments approved for other indications by the US FDA (or other regulatory bodies) (antipsychotics, antidepressants, and mood stabilizers), brain stimulation, and behavioral- and activity-based approaches, including physical exercise. Potential complications regarding the design of current negative symptom trials are discussed and include inconsistent placebo effects, lack of reliable biomarkers, negative symptom scale and inclusion criteria variability, attempts to distinguish between primary and secondary negative symptoms, lack of focus on early psychosis, and the potential iatrogenic bias of clinical trials.

Dysfunction of neuroplasticity due to N-methyl-d-aspartate (NMDA) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia. Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms. Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study. We evaluate effects of memantine add-on treatment to clozapine for memory and executive function, and negative and positive symptoms in schizophrenia.

Clozapine-treated patients with refractory schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (n = 26) or placebo (n = 26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale.

When compared with placebo, memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) and PANSS negative subscale score (effect size = 0.29). Side effects were mild and transient.

In patients with clozapine-treated refractory schizophrenia, memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects. These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia.

Subjective memory complaints (SMCs) are common in older adults that can often predict further cognitive impairment. No proven effective agents are available for SMCs. The effect of BrainPower Advanced, a dietary supplement consisting of herbal extracts, nutrients, and vitamins, was evaluated in 98 volunteers with SMCs, averaging 67 years of age (47-88), in a randomized, double-blind, placebo-controlled trial. Subjective hypomnesis/memory loss (SML) and attention/concentration deficits (SAD) were evaluated before and after 12-week supplementation of BrainPower Advanced capsules (n = 47) or placebo (n = 51), using a 5-point memory questionnaire (1 = no/slight, 5 = severe). Objective memory function was evaluated using 3 subtests of visual/audio memory, abstraction, and memory recall that gave a combined total score. The BrainPower Advanced group had more cases of severe SML (severity ⩾ 3) (44/47) and severe SAD (43/47) than the placebo group (39/51 and 37/51, < 0.05, < 0.05, resp.) before the treatment. BrainPower Advanced intervention, however, improved a greater proportion of the severe SML (29.5%)(13/44) (P < 0.01) and SAD (34.9%)(15/43)(P < 0.01) than placebo (5.1% (2/39) and 13.5% (5/37), resp.). Thus, 3-month BrainPower Advanced supplementation appears to be beneficial to older adults with SMCs.

It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue.

A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups.

A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy.

Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.