A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

Correll, Christoph U.; Agid, Ofer; Crespo‐Facorro, Benedicto; Bartolomeis, Andrea de; Fagiolini, Andrea; Seppälä, Niko; Howes, Oliver

doi:10.1007/s40263-022-00932-2

Cited by 63 publications

(61 citation statements)

References 168 publications

(183 reference statements)

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“…On the other hand, atypical antipsychotics, including quetiapine, olanzapine, and clozapine, were effective in regulating the cortical expression of IEGs, specifically BDNF in the hippocampus and PFC [ 103 , 104 , 105 , 106 , 107 , 108 ], as well as affecting subcortical stations, including dorsal and ventral striatum [ 87 , 88 ]. Clozapine, the only drug approved for treatment-resistant schizophrenia [ 156 ], was found to fine-tune cortical functional connectivity, neuronal synchrony in high-gamma bands, and PFC-medial ventral striatum coherence by reverting the alterations induced by PCP and ketamine in preclinical models via modulation of serotonin receptors [ 40 , 127 , 129 , 134 ]. Therefore, the beneficial action of first-generation compounds on psychotic symptoms may rely on their capability to modulate subcortical-cortical networks by tackling the dopamine receptors sited at the striatal pathways, whereas clozapine and other atypical antipsychotics may mainly target functional circuits linking the hippocampus and ventral striatum with the PFC [ 8 , 9 , 128 , 129 , 134 ].…”

Section: Discussionmentioning

confidence: 99%

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Bartolomeis¹,

Simone²,

Ciccarelli³

et al. 2022

Biomedicines

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Schizophrenia is a severe mental illness characterized by alterations in processes that regulate both synaptic plasticity and functional connectivity between brain regions. Antipsychotics are the cornerstone of schizophrenia pharmacological treatment and, beyond occupying dopamine D2 receptors, can affect multiple molecular targets, pre- and postsynaptic sites, as well as intracellular effectors. Multiple lines of evidence point to the involvement of antipsychotics in sculpting synaptic architecture and remodeling the neuronal functional unit. Furthermore, there is an increasing awareness that antipsychotics with different receptor profiles could yield different interregional patterns of co-activation. In the present systematic review, we explored the fundamental changes that occur under antipsychotics’ administration, the molecular underpinning, and the consequences in both acute and chronic paradigms. In addition, we investigated the relationship between synaptic plasticity and functional connectivity and systematized evidence on different topographical patterns of activation induced by typical and atypical antipsychotics.

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Section: Discussionmentioning

confidence: 99%

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Bartolomeis¹,

Simone²,

Ciccarelli³

et al. 2022

Biomedicines

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“…Furthermore, the higher odds of comorbidities such as diabetes, obesity, and seizure disorder, as well as debilitating adverse effects such as constipation, excessive sedation, problem swallowing and sialorrhea, always require consideration at baseline before initiation of clozapine (Siskind et al, 2017). Many clozapine adverse effects can be managed by proper dosing, therapeutic drug monitoring and pharmacological/non-pharmacological interventions, and they need not be a barrier for individuals with treatment-resistant SSD and SUDs (Correll et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

et al. 2022

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Background: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes. Aim: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine. Methods: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using “Downs and Black,” and “Q-Coh” instruments. Results: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study. Conclusions: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

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“…More than 65 years after its discovery and more than 30 years after the seminal study by Kane and colleagues 8 , clozapine remains the only effective antipsychotic drug for patients with treatment-resistant schizophrenia (TRS) [9][10][11][12] . Moreover, the superior efficacy of clozapine for crucial clinical aspects of schizophrenia beyond narrowly defined treatment resistance is very well established [13][14][15] . Although these findings are reflected in all major national and international treatment guidelines [16][17][18][19][20] , converging evidence from developed countries clearly indicates that clozapine remains substantially underused 21 .…”

Section: Introductionmentioning

confidence: 99%

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

Qubad¹,

Bittner²

2022

Preprint

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Despite its continued relevance as the single most effective and important evidence-based treatment for schizophrenia, the degree of underutilization of clozapine across health systems remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to use clozapine due to its relatively large side-effect burden and its comparatively complex dosing and monitoring requirements. This underscores the necessity for continued education of clinicians in the intricacies of clozapine use and in the still growing case in favor of this vital treatment option. Consequently, this narrative review provides a comprehensive outline of all lines of evidence, which support clozapine’s wide-ranging superior efficacy, and of the current knowledge regarding the prevalence and diagnosis of treatment resistance. The distinct neurobiological and clinical characteristics of this condition makes the swift initiation of clozapine indispensable. Moreover, we review the extensive literature regarding clozapine’s side effect profile and current recommendations for optimal treatment and monitoring algorithms including for particularly vulnerable populations such as elderly patients and pregnant women and for potential re-challenges after myocarditis and neutropenia. We also discuss established approaches to increase treatment response as well as augmentation strategies for patients with partial or full clozapine resistance. We argue for a clear focus on early and consistent detection and management of side effects, which can ensure patient safety and reduce permanent all-cause discontinuation. This strategy needs to be combined with a long-term approach acknowledging the late onset of clozapine’s full advantageous effects, which – in cases like reduced mortality rates – even then may not be easily discernible. Our aim is to encourage a safer, more frequent, and timely use of clozapine to maximize patients’ short- and long-term benefits. Even now, the extent of these benefits as well as patient’s satisfaction with treatment still clearly set clozapine apart from all other available treatment options.

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A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

Cited by 63 publications

References 168 publications

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

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