Correction to: Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment

Background: The clozapine-derivative quetiapine has been shown in some cases to cause leukopenia and neutropenia. Case Presentation: We reported on a case of a young female diagnosed with treatment-resistant schizophrenia. After failed trials of three antipsychotic medications and despite a history of quetiapineinduced leukopenia, clozapine treatment was introduced due to the severity of the patient’s symptoms, the limited effective treatment options, and a lack of guidelines on this issue. Result: Over a ten-week period of clozapine treatment at 700 mg per day, the patient developed agranulocytosis. Her white blood cell count sharply dropped to 1.6 × 10<sup>9</sup> L, and her neutrophils decreased to 0.1 × 10<sup>9</sup> L. There had been no similar reaction to her previous medications (carbamazepine, risperidone, and haloperidol). Conclusion: The safety of clozapine in a patient who has previously experienced leukopenia and neutropenia with quetiapine requires further investigation. Increased attention should be paid to such cases. Careful monitoring and slow titration are advisable.

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An evaluation of barriers to the initiation of clozapine in patients with treatment-resistant schizophrenia

BJPsych Open ◽

10.1192/bjo.2021.135 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S30-S31

Author(s):

Declan Hyland ◽

Seth Jamieson

Keyword(s):

Systematic Review ◽

Significant Progress ◽

Treatment Resistant ◽

The South ◽

Online Questionnaire ◽

Blood Testing ◽

Likert Scales ◽

Clozapine Treatment ◽

Patient Barriers ◽

Made In

AimsThis evaluation aimed to identify patient, practitioner and infrastructural barriers to initiation of clozapine treatment in patients with treatment-resistant schizophrenia (TRS). In response to recent research supporting use of clozapine as the most effective treatment for patients with TRS, concerted efforts have been made to establish why clozapine is underutilised in the NHS. Following a study conducted by South London and Maudsley NHS Foundation Trust, which identified barriers and made recommendations, this evaluation aimed to identify barriers to initiation of clozapine in patients under the care of Mersey Care NHS Foundation Trust.This evaluation also aimed to make further recommendations to increase use of clozapine in Mersey Care's TRS patients and assess whether there have been any differences to concerns about clozapine initiation compared to previous evaluations.MethodAn online questionnaire containing a series of Likert scales was e-mailed to all Consultant Psychiatrists in Mersey Care NHS Foundation Trust. The questionnaire asked Consultants to rate how often they felt a range of barriers interfered with successful initiation of Clozapine treatment. The barriers chosen were based on the 2019 systematic review “Barriers to using clozapine in treatment-resistant schizophrenia.”ResultNineteen consultant psychiatrists completed the online questionnaire. All 19 indicated they either “agreed” (16%) or “strongly agreed” (84%) that they were confident in diagnosing TRS. This was a significant increase compared to the South London and Maudsley evaluation, with only 81% of participants in that study being “fairly familar” or “very familiar” with clozapine guidelines.Furthermore, concerns about inadequate blood testing facilities appear to have been addressed, with no participants in this evaluation staing there were insufficient blood testing facilities. However, 53% of Consultants who completed this evaluation stated they “often” (37%) or “very often” (16%) have patients who refuse clozapine because of the requirement for regular blood testing. Refusal to agree to required blood testing was the commonest reason identified for failure to initiate clozapine in TRS patients. This was consistent with the results from the South London and Maudsley study.ConclusionThose Mersey Care consultants surveyed identified that providing patients with further information about clozapine would be the most valuable intervention to increase likelihood of uptake of clozapine in the treatment of TRS. Significant progress has been made in improving the likelihood that clozapine can be successfully initiated, especially in the removal of practitioner barriers. This evaluation suggests interventions should now be aimed at reducing patient barriers to initiation of treatment.

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Clozapine: A Case Vignette

Australasian Psychiatry ◽

10.3109/10398569609082080 ◽

1996 ◽

Vol 4 (6) ◽

pp. 336-337

Author(s):

Ilana Nayman

Keyword(s):

Young Woman ◽

Psychiatric Practice ◽

Case Vignette ◽

Treatment Resistant ◽

Symptom Resolution ◽

Clozapine Treatment ◽

Level Of Functioning ◽

History Of ◽

High Level

This paper describes successful clozapine treatment in a young woman with a five year history of treatment-resistant schizophrenia. After various treatment-resistant strategies had been given, clozapine was commenced. Symptom resolution within 4 months and sustained high level of functioning within 7 months was achieved. The role of clozapine in general psychiatric practice is evident. Clozapine should be considered earlier in the illness course than was formerly the case.

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Successful rechallenge with paliperidone after clozapine treatment for a patient with dopamine supersensitivity psychosis

SAGE Open Medical Case Reports ◽

10.1177/2050313x20929561 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2092956

Author(s):

Remiko Kobayashi ◽

Yasunori Oda ◽

Ryunosuke Hayatsu ◽

Nozomi Ohki ◽

Misa Akutsu ◽

...

Keyword(s):

Symptomatic Relief ◽

Psychotic Symptoms ◽

Psychotic Episode ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Clozapine Treatment ◽

Clozapine Dose ◽

Japanese Male ◽

Old Japanese ◽

Dopamine Supersensitivity

We describe the case of a 49-year-old Japanese male patient successfully treated with a paliperidone rechallenge following 2-year treatment with clozapine for treatment-resistant schizophrenia. He had responded well to conventional antipsychotic treatment for the initial psychotic episode but gradually developed dopamine supersensitivity; even treatment with paliperidone and another antipsychotic medication (a total up to 1700 mg in chlorpromazine-equivalent dose) had not improved his psychotic symptoms. Clozapine treatment produced temporary symptomatic relief, but the clozapine dose could not be increased to > 150 mg due to the patient’s intolerance. Following low-dose clozapine treatment for 2 years, a rechallenge with paliperidone monotherapy ameliorated his psychotic symptoms. This suggests that clozapine may have the potential to release the dopamine supersensitivity state. Our patient’s case indicates that for patients with dopamine supersensitivity psychosis, a rechallenge with a previously ineffective antipsychotic after clozapine treatment may be successful.

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Resolution without discontinuation: heart failure during clozapine treatment

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125320924786 ◽

2020 ◽

Vol 10 ◽

pp. 204512532092478 ◽

Cited By ~ 1

Author(s):

Eromona Whiskey ◽

Shirley Yuen ◽

Emma Khosla ◽

Susan Piper ◽

David O’Flynn ◽

...

Keyword(s):

Heart Failure ◽

Psychotic Disorders ◽

Cardiac Complications ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Clozapine Treatment ◽

Cardiac Condition ◽

Life Threatening ◽

Psychotic Exacerbation ◽

Cessation Of Treatment

Clozapine is an atypical antipsychotic recommended for patients with treatment-resistant schizophrenia whose illness has not responded adequately to treatment despite the sequential use of at least two different antipsychotic drugs at therapeutic doses. Unfortunately, clozapine is frequently discontinued due to both real and perceived serious, and potentially life-threatening, adverse effects, contributing to the underutilisation of the most effective treatment in refractory psychotic disorders. Here, we present the case of a 51-year-old man with treatment-resistant schizoaffective disorder, who was admitted to a locked rehabilitation unit for a clozapine rechallenge. Within 6 months after the clozapine rechallenge, he was diagnosed with heart failure likely secondary to his antipsychotic treatment. Clozapine-induced heart failure usually prompts immediate cessation of treatment. However, in this case, clozapine was continued with cardiology consultation. Ramipril and bisoprolol were initiated and the patient’s cardiac condition progressively improved over time. Clozapine-induced heart failure is a serious cardiovascular complication of treatment, usually resulting in discontinuation of treatment. Although there are cases of successful rechallenge, temporary cessation of treatment can lead to severe psychotic exacerbation and non-engagement with cardiac specialists. More evidence is required for continued use of clozapine in a patient with clozapine-induced cardiac complications.

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S170. PROGRESSIVE SUBCORTICAL VOLUME LOSS IN TREATMENT-RESISTANT SCHIZOPHRENIA PATIENTS AFTER COMMENCING CLOZAPINE TREATMENT

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.236 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S101-S102

Author(s):

Giulia Tronchin ◽

Theophilus N Akudjedu ◽

Mohamed Ahmed ◽

Brian Hallahan ◽

Dara M Cannon ◽

...

Keyword(s):

Volume Reduction ◽

Symptom Improvement ◽

Treatment Resistant ◽

Subcortical Structures ◽

Clinical Variables ◽

Clozapine Treatment ◽

Subcortical Brain ◽

Subcortical Volumes ◽

Over Time

Abstract Background The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. Early studies investigating a switch from first generation antipsychotic to clozapine have steadily shown a decrease of caudate volume over time; however nowadays most patients are already on second generation antipsychotic medications prior to clozapine commencement and it remains unclear whether switching to clozapine in such circumstances would have any such effect on the basal ganglia. In this study we aimed to comprehensively investigate whether after 6 months of switching to clozapine, subcortical structures demonstrate any progressively neuroanatomical changes in patients with treatment-resistant schizophrenia compared to healthy controls, and whether any such changes are related to clinical variables including treatment response and amount of clozapine taken. Methods MRI images were acquired for all participants at baseline and after 6 months at University Hospital Galway in a 1.5 T scanner. The longitudinal pipeline of Freesurfer v.5.3.0, based on an unbiased within-subject anatomical template, was employed to segment eight subcortical regions-of-interest: lateral ventricle, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala and nucleus accumbens. Subcortical volumes were bilaterally extracted following quality check of raw data and segmentation. Clinical assessments included the Positive and Negative Syndrome Scale (PANSS), The Scale for the Assessment of Positive Symptoms (SAPS), The Scale for the Assessment of Negative Symptoms (SANS) and Global Assessment Functioning Score (GAF). Two-way repeated ANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Change in volume was expressed using the following formula: (Follow Up -Baseline)/Baseline x 100. Results 33 patients with treatment-resistant schizophrenia (TRS) and 31 healthy volunteers (HC) matched for sex and age were successfully recruited at both baseline prior to clozapine treatment and after 6 months. There was a significant effect of time on subcortical brain volumes between TRS and controls (F(7,143)= 52.54, p<0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59)= 48.89; p<0.001) and reduction of thalamus (F(1,59)= 34.85; p<0.001), caudate (F(1,59)= 59.35; p<0.001), putamen (F(1,59)= 87.20; p<0.001) and hippocampus (F(1,59)= 14.49; p<0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r=0.42; p=0.021, r=0.39; p=0.033), SANS (r=0.36; p=0.049, r=0.40; p=0.027) and GAF (r=-0.39; p=0.038, r=-0.42; p=0.024). Reduced thalamic volume over time was associated with increased serum level at follow-up (r=-0.44; p=0.010). There was no significant overall effect of time on subcortical brain structures between patients responding to clozapine compared to patients non-responding to clozapine (F(7,20)=0.50; p=0.834). Discussion This study demonstrates that, despite the clinical and functional improvement of most patients with schizophrenia who are switched to clozapine, there is a counterintuitive progressive volume reduction in several subcortical structures over time. Furthermore, patients who have the greatest symptomatic improvement display the largest thalamo-putaminal reductions, indicating that volume reduction reflects an adaptive response associated with symptom improvement rather than a harmful or neurotoxic process in these patients.

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S1. CLOZAPINE RECHALLENGE FOLLOWING NEUTROPENIA USING GRANULOCYTE COLONY-STIMULATING FACTOR: A QUEBEC CASE SERIES

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.067 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S30-S30

Author(s):

Laurent Béchard ◽

Olivier Corbeil ◽

Maude Plante ◽

Marc-André Thivierge ◽

Charles-Émile Lafrenière ◽

...

Keyword(s):

Neutrophil Count ◽

Demographic Data ◽

Case Series ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Treatment Resistant ◽

Previous Response ◽

Response Level ◽

Clozapine Treatment ◽

Stimulating Factor

Abstract Background Clozapine possesses unique efficacy profile in treatment-resistant schizophrenia but is associated with neutropenia and agranulocytosis, in respectively, 3% and 0.7% of exposed patients. Granulocyte colony-stimulating factor (G-CSF) has been used to allow clozapine continuation or rechallenge in such situation (1,2). Methods We aim to describe the use of G-CSF to maintain clozapine despite neutropenia or agranulocytosis in treatment resistant schizophrenia patients in Quebec province, Canada. A national clozapine hematological monitoring database was consulted to identify all patients who have had red event (neutrophil count < 1,5 threshold) since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who have received at least one dose of G-CSF while been exposed to clozapine All patients with an active cancer diagnosis while taking clozapine and G-CSF were excluded. A group of pharmacists specialized in psychiatry in Quebec was also contacted to ensure selecting all cases in the province. In additional to demographic data and clozapine and G-CSF details, Clinical Global Impression severity scale (CGI-S) was used to evaluate psychopathology severity during four critical turning points: before and after clozapine introduction, after agranulocytosis episode and after clozapine rechallenge. All data were collected retrospectively, using patient’s medical files, from January to July 2019. Results Eight (8) patients (5 males, 3 females), Caucasian, mean age 48 years old, with clozapine median exposition of 4.8 years, were identified. In 7/8 of those, G-CSF was used according to an “as required strategy”, i.e., whenever the patient’s neutrophil count dropped below a pre-determined threshold, varying according to patient between 0,8 à 1,5. In the other patient, a 3-weekly doses were preventively administered. Despite this, a mean number of 4 red events (ranging from 1 to 10 events) were subsequently observed in those patients, leading to clozapine cessation in 4/8 patients. One other patient responded to G-CSF but the clinical team felt uncomfortable to maintain clozapine in such circumstances. No complication (infection for instance) due to low neutrophil counts was observed nor any significant side effect related to G-CSF. However, in all these cases, while clozapine treatment was associated with clinically significant improvement of psychopathology (mean CGI-S decreased from 5.5 to 3.4), clozapine cessation led to an important psychotic deterioration (mean CGI-S of 6.2) at follow up. Fortunately, in patients successfully rechallenged (3/8), a strong clinical improvement was observed, with return to previous response level observed. Discussion To our knowledge, this is the largest case series of clozapine rechallenge using G-CSF and adds to the 39 already described cases in which G-CSF was concomitantly used with clozapine (1,2). While an “as required” strategy was mainly used here, a different prophylactic G-CSF use may have led to higher rates of clozapine maintenance, despite red codes, which provides the impetus for further studies. Reference

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Ten years' experience with clozapine in treatment-resistant schizophrenic patients: Factors indicating the therapeutic response

European Psychiatry ◽

10.1016/s0924-9338(97)83577-8 ◽

1997 ◽

Vol 12 (S5) ◽

pp. 343s-346s ◽

Cited By ~ 8

Author(s):

E Alvarez ◽

F Barón ◽

J Perez-Blanco ◽

D Puigdemont José Soriano ◽

C Masip ◽

...

Keyword(s):

Social Adjustment ◽

Therapeutic Response ◽

Rating Scale ◽

Good Prognosis ◽

Average Dose ◽

Treatment Resistant ◽

Clozapine Treatment ◽

Before And After ◽

Schizophrenic Patients ◽

A Prospective Study

SummaryA prospective study in treatment-resistant schizophrenic patients was performed over 10 years to evaluate the therapeutic response to clozapine and the variables related to this treatment. Eighty schizophrenic and schizoaffective patients (according to Diagnostic and Statistical Manual [DSM]-IIIR criteria), considered as refractory (previously resistant to at least two different typical neuroleptics), were studied. The average dose of clozapine was 267 mg/d. The clinical variables considered were: Brief Psychiatric Rating Scale (BPRS), number of admissions before and after clozapine treatment and the Strauss-Carpenter scale as measures of efficacy; Premorbid Adjustment Scale (PAS), to assess personal and social adjustment before illness; Karolinska Personality Scale (KPS) to assess stable traits of personality; and the Simpson-Angus scale as a measure of extrapyramidal symptoms. Sixty percent of patients showed a significant improvement after clozapine treatment. Side-effects were mild and well tolerated, with no cases of haematological disturbance and only five withdrawals because of adverse events. The severity of the episode, according to BPRS score and anxiety as a personal trait, are related to good prognosis. Other relationships between improvement and clinical and demographic variables are discussed.

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