Duration of prior psychotic illness and clozapine response: a retrospective observational study using electronic health records

Jones, Rowena; Upthegrove, Rachel; Price, Malcolm J; Pritchard, Megan; Chandan, Joht Singh; Legge, Sophie E.; MacCabe, James H.

doi:10.1177/20451253221103353

“… 66 , 67 Clinical efficacy of clozapine depends crucially on early treatment initiation. 66 , 68 – 70 Response rates for treatment initiation within the first 2–3 years after establishing treatment resistance can reach up to 80%. 64 , 66 , 71 For later treatment initiation, response rates can be as low as 30%.…”

Section: Clinical Effects Of Clozapinementioning

confidence: 99%

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Qubad

¹

,

Bittner

²

2023

Therapeutic Advances in Psychopharmacology

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Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine’s wide-ranging superior efficacy – for treatment-resistant schizophrenia (TRS) and beyond – and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients’ benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine’s unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine’s full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

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“…The delay in initiating clozapine (DIC) after establishing treatment resistance, which is estimated at around 5–7 years, has important prognostic value [6 ▪▪ ,7,8,22]. After a DIC of more than 2–4 years response rates can decline considerably [6 ▪▪ ], whereas a short DIC is associated with response rates of up to 80% [44]. The impact of the DIC mirrors the well established prognostic value of the duration of untreated psychosis (DUP) [45], which also constitutes a risk factor for treatment resistance [46,47].…”

Section: The Delay In Initiating Clozapinementioning

confidence: 99%

“…The delay in initiating clozapine (DIC) after establishing treatment resistance, which is estimated at around 5–7 years, has important prognostic value [6 ▪▪ ,7,8,22]. After a DIC of more than 2–4 years response rates can decline considerably [6 ▪▪ ], whereas a short DIC is associated with response rates of up to 80% [44].…”

Section: The Delay In Initiating Clozapinementioning

confidence: 99%

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The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry

Bittner

¹

,

Reif

²

,

Qubad

³

2023

Current Opinion in Psychiatry

6

0

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Purpose of reviewClozapine remains the gold standard for treatment-resistant schizophrenia (TRS). Although the evidence base for its wide-ranging, unique efficacy continues to expand, clozapine remains alarmingly underutilized in industrialized countries. Analyzing the causes and consequences of this problem is crucial for substantially improving the quality of care for TRS patients.Recent findingsClozapine is the most effective antipsychotic for reducing all-cause mortality in TRS. In most cases, treatment resistance emerges during the first psychotic episode. Delaying clozapine treatment has a negative impact on long-term outcome. Patients’ experience with clozapine treatment is largely positive despite a comparatively high rate of side effects. Patients prefer clozapine, while psychiatrists regard it as a burden due to concerns regarding safety and side effect management. Shared decision-making (SDM), which increases the likelihood of a clozapine recommendation, is not routinely used, possibly due to stigmatization of TRS patients.SummaryThe mortality-reducing effects of clozapine alone warrant its regular use. Therefore, psychiatrists must not exclude patients from the decision regarding a clozapine trial by not even offering it. Rather, they have a clear obligation to align their actions more closely with the existing evidence and patients’ needs and to facilitate the timely initiation of clozapine.

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“…Moreover, aberrations in immune-inflammatory pathways have been found to play a role in TRS 11 with specific signatures in this population 12 . In this line, immunological mechanisms may also contribute to treatment response to antipsychotics 13 , and clozapine may exert its superior efficacy via immune mechanisms 14 .…”

Section: Introductionmentioning

confidence: 99%

Blood Cell Count Ratios at Baseline are Associated with Initial Clinical Response to Clozapine in Treatment-Resistant, Clozapine-Naïve, Schizophrenia-Spectrum Disorder

Llorca-Bofí,

Bioque,

Madero

et al. 2024

Pharmacopsychiatry

2

0

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Background Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS. Methods A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit. Results Baseline NLR (b=− 0.364; p=0.041) and MLR (b =− 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up. Conclusion Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings.

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Duration of prior psychotic illness and clozapine response: a retrospective observational study using electronic health records

Cited by 5 publications

References 43 publications

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry

Blood Cell Count Ratios at Baseline are Associated with Initial Clinical Response to Clozapine in Treatment-Resistant, Clozapine-Naïve, Schizophrenia-Spectrum Disorder

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