Introduction
Although clozapine remains the only evidence-based
pharmacological treatment for treatment-resistant schizophrenia
(TRS) (1-4),
decades of debate regarding potentially fatal side effects,
especially agranulocytosis, continue to generate hesitation among
clinicians and have not resulted in increased clozapine
utilization, despite accumulating supportive evidence (4-6).
TRS represents a major clinical challenge, and clozapine remains
the gold standard for its management. Several factors, including
sex, age, smoking habits and metabolic capacity, may influence
clozapine and norclozapine serum concentration variability
(1,7-10).
The rationale for the present study stems from findings of the
multicentric CLOSER study (11),
which investigated clozapine plasma levels and outcomes in Serbian
patients with treatment-resistant psychotic disorders treated
without therapeutic drug monitoring (TDM). While that study
provided valuable preliminary insights, it included patients from
three different centers and covered a broader diagnostic spectrum,
introducing institutional and demographic variability.
By contrast, the current study focuses on a
localized and diagnostically homogeneous cohort of 43 patients with
TRS, treated at the Special Hospital for Psychiatric Disorders
‘Kovin’ (SBPB Kovin), allowing for a more detailed evaluation of
clozapine and norclozapine serum level variability, clinical scales
and adverse effects. This targeted and context-specific design
provides complementary evidence to the broader multicentric CLOSER
dataset and enables more precise identification of factors
contributing to interindividual pharmacokinetic variability and
treatment outcomes in this specific population. Understanding these
factors is essential for optimizing dosing strategies and improving
therapeutic outcomes. Importantly, studies have shown that the
occurrence of subjective side effects is not directly related to
clozapine dosage (12-14).
A significant but weak correlation has been observed between side
effects and plasma clozapine concentrations (14). Seppälä et al (13) also reported an association between
elevated norclozapine levels and symptoms of depression/anxiety,
although causality could not be determined. Clozapine, particularly
in TRS, has demonstrated superiority in improving quality of life
and symptomatology, though data on its effects on functional
disability remain limited (15,16).
In numerous countries, including Serbia, TDM for
clozapine is not routinely available. This limitation contributes
to underutilization of clozapine or, when it is used, to avoidance
of higher therapeutic doses due to fear of adverse effects.
Consequently, dosage adjustments are often based solely on clinical
judgment, which may increase the risk of therapeutic failure or
adverse outcomes (17).
Patients on clozapine require regular clinical
monitoring obligation, including physical examinations and
laboratory testing, to minimize the risk of side effects (18,19).
Monitoring plasma concentrations of clozapine and its metabolite
norclozapine enhances treatment safety and efficacy, supports
adherence, and reduces the risk of toxicity (20). The timely detection of numerous
previously overlooked side-effects has significantly improved
wherever after clinicians implemented the Glasgow scale for
clozapine side effects scale (12),
that has been well validated and translated into Serbian (21). Clozapine is metabolized into
N-desmethylclozapine (norclozapine) primarily by cytochrome P450
1A2, with lesser involvement of CYP3A4, 2D6, 2C9 and 2C19(7).
Schizophrenia, a disorder that affects cognition,
affect, perception and thought content, is one of the leading
causes of long-term disability worldwide (22). Up to 80% of patients experience
functional impairments across multiple life domains (23).
The aim of the present study is to assess the
association between serum concentrations of clozapine and
norclozapine-measured with the Dried Blood Spot (DBS) method - and
symptom severity, functionality, disability and side effects in
Serbian inpatients with TRS.
Materials and methods
Study design and participants
The present cross-sectional study is part of a
larger multi-center investigation, with previously published
preliminary findings involving patients with schizophrenia and
schizoaffective disorder focusing on relationship between clozapine
levels and outcomes and clozapine level above the laboratory-alert
level (11). Given the
controversies of the nosological entity of schizoaffective disorder
(24), and that current clinical
recommendations are based on data from large trials in
schizophrenia or extrapolations from samples of bipolar or
schizophrenic patients (25). In
the present study, focus was addressed exclusively on data from 43
adult patients diagnosed with TRS, treated at the SBPB Kovin,
Serbia. All participants had been receiving a stable clozapine dose
for at least three months, either as inpatients or outpatients.
Written informed consent was obtained in line with the Declaration
of Helsinki and Good Clinical Practice guidelines, following
ethical approval by the SBPB Kovin Ethics Committee (approval no.
01-3615/3-3659/1; dated 29.11.2017; Kovin, Serbia).
Inclusion and exclusion criteria
Inclusion criteria were: (i) Diagnosis of
schizophrenia (ICD-10 codes F20.0-F20.9); (ii) age: 18-55 years;
(iii) documented treatment resistance (non-response to at least two
different antipsychotics) (26);
and (iv) ongoing clozapine therapy. Exclusion criteria included:
(i) Psychotic disorders outside the schizophrenia spectrum; (ii)
bipolar or unipolar mood disorders; (iii) organic psychoses and
(iv) substance-induced psychotic disorders.
Demographic data
Demographic information included: Sex, age, Body
Mass Index (BMI), obesity, education level, employment status,
marital status, coffee and energy drink consumption.
Clozapine therapy profile
Information was collected on clozapine dosage (daily
and number of doses), as well as clozapine and norclozapine
concentrations.
Clinical data
Clinical history data included the place of
treatment and number of psychiatric hospitalizations. The following
standardized clinical instruments were used: GASS-C (Clozapine
Adverse Effects Scale, Serbian version): Evaluates the frequency
and distress of 16 common clozapine-related side effects on a 0-3
Likert scale over the past 7 days. Severity levels are categorized
as mild, 0-16; moderate, 17-32; and severe, 33-48. Internal
consistency: Cronbach's α=0.82(21).
WHODAS 2.0 (Disability Assessment Scale):
Assesses disability across multiple domains (27,28).
Scores range from 1 (no difficulty) to 5 (extreme difficulty).
Clinical Global Impression-Severity (CGI-S):
Clinician-rated global measure of illness severity on a 7-point
scale (29).
Global Assessment of Functioning (GAF):
Evaluates social, occupational, and psychological functioning,
ranging from 1 (severe impairment) to 100 (optimal functioning)
(30,31).
Simplified Interview for Positive and Negative
Symptoms (SNAPSI): A structured interview tool designed to
extract ratings from Brief Psychiatric Rating Scale (29), PANSS-6, and other scales, including
integration of collateral information (32-35).
All assessments were performed by a single psychiatrist with
extensive experience using the aforementioned instruments. Only
validated Serbian-language versions of all scales were used.
Clozapine and norclozapine level
determination
Clozapine and norclozapine concentrations were
measured using the DBS method, which is cost-effective and suitable
for resource-limited settings. DBS has been validated for
clozapine, making TDM of clozapine accessible in parts of the world
where it is currently unavailable. Single-layer filter paper cards
(Whatman 903) were used, with correction factors applied to account
for cellular components. DBS samples were obtained from venous
blood collected at SBPB Kovin, following standard sampling
procedures (36-38).
Statistical analysis
Statistical analyses were conducted using SPSS v19
(IBM Corp.). Descriptive statistics were used for all variables.
Group comparisons were performed using independent-samples t-tests
or Mann-Whitney U-tests for two groups, and one-way ANOVA one-way
or Kruskal-Wallis tests for three or more groups. Associations
between categorical variables were analysed using Chi-square or
Fisher's exact tests. Correlations between numerical variables were
evaluated using Spearman's correlation coefficient ρ. Multivariate
linear regression was used to determine predictors of GASS-C and
WHODAS scores. P<0.05 was considered to indicate a statistically
significant difference.
Results
The demographic and clinical characteristics of the
43 patients with TRS treated with clozapine are included in
Table I. Our sample primarily
consisted of middle-aged patients, with a predominance of males
(76.7%) over females (23.3%), and a long duration of illness and
hospitalizations. This 3:1 male-to-female ratio reflects the local
institutional population and may also align with meta-analytic
evidence indicating a higher likelihood of TRS in men (39). Sex differences, including smoking
habits and metabolic profiles, are relevant for interpreting
clozapine and norclozapine concentrations (1,7-10,15).
Most patients were smokers, with a mean BMI of 26.28±5. These
characteristics are consistent with previously described TRS
populations.
 | Table IDemographic, clinical characteristics
and profile of clozapine therapy in patients with
treatment-resistant schizophrenia. |
Table I
Demographic, clinical characteristics
and profile of clozapine therapy in patients with
treatment-resistant schizophrenia.
| Demographic
characteristics | Mean ± SD or N
(%) |
|---|
| Sex | |
|
Male | 33 (76.7%) |
|
Female | 10 (23.3%) |
| Age, years | 51.35±10.11 |
| Obesity | |
|
Male | 0.0% |
|
Female | 24.2% |
| Body mass index
(kg/m2) | 26.28±5.04 |
| Coffee (daily) | 2.79±1.08 |
| Coke (weekly, in
liters) | 0.10±0.32 |
| Cigarettes
(daily) | 17.67±12.12 |
| Marital status | |
|
Single | 29 (67.4%) |
|
Married | 7 (16.3%) |
|
Divorced/widowed | 7 (16.3%) |
| Educational
level | |
|
No formal
education | 4 (9.3%) |
|
Primary
school | 13 (30.2 %) |
|
Vocational
education | 7 (16.3%) |
|
High school
8-12 | 19 (44.2%) |
|
College
12-16 | 3 (7.0%) |
|
University | 1 (2.3%) |
| Employment
status | |
|
Unemployed | 21 (48.8%) |
|
Pensioner | 22 (51.2%) |
| Clinical
characteristics | Mean ± SD or N
(%) |
| Number of
hospitalizations | |
|
1 | 20 (46.5%) |
|
2 | 23 (53.5%) |
| Place of
treatment | |
|
Hospital | 36 (83.7%) |
|
Health care
center | 7 (16.3%) |
| GASS-C | 3.14±4.039 |
| WHODAS | 12.28±10.64 |
| CGI-S | 4.67±1.017 |
| GAF | 54±14.5 |
| SNAPSI | 19.07±5.351 |
| Clozapine therapy
profile | N (%) or median
(25-th percentile - 75-th percentile) |
| Daily clozapine
dose frequency | |
|
1 | 4 (9.3%) |
|
2 | 24 (55.8%) |
|
3 | 15 (34.9%) |
| Clozapine dose
(mg/d) | 200.00
(150.00-300.00) |
| Clozapine
concentration (ng/ml) | 309.40
(147.09-507.93) |
| Norclozapine
concentration (ng/ml) | 133.39
(71.40-207.57) |
The association between clozapine side effects
(assessed by GASS-C) and demographic, clinical characteristics and
clozapine treatment profile are demonstrated in Table II. Patients with only one
hospitalization tended to have higher levels of side effects
compared with those with multiple hospitalizations, although this
difference was not statistically significant (P=0.055). Notably,
higher body mass and BMI were significantly associated with fewer
side effects (GASS-C scores) (ρ=-0.613, P<0.0005; ρ=-0.678,
P<0.0005, respectively, where ρ is Spearman's correlation
coefficient and P is probability). Conversely, higher disability
levels (WHODAS scores) correlated positively with the severity of
side effects (ρ=0.372, P=0.014).
| Table IIAssociation of adverse effects of
clozapine with demographic, clinical characteristics and profile of
clozapine therapy in patients with treatment-resistant
schizophrenia. |
Table II
Association of adverse effects of
clozapine with demographic, clinical characteristics and profile of
clozapine therapy in patients with treatment-resistant
schizophrenia.
| | GASS-C |
|---|
| Variables | N | Mean ± SD | t-test | P-value |
|---|
| Sex | | | 4.434 | 0.003 |
|
Male | 33 | 1.85±2.93 | | |
|
Female | 10 | 7.40±4.40 | | |
| Obesity | | | 10.931 | 0.001 |
|
No | 24 | 3.38±4.42 | | |
|
Yes | 8 | 0.00±0.00 | | |
| Number of
hospitalizations | | | 3.892 | 0.055 |
|
1 | 20 | 4.40±4.99 | | |
|
2 | 23 | 2.04±2.64 | | |
| Number of clozapine
doses | | | 5.515 | 0.008 |
|
1 | | 0.00±0.00 | | |
|
2 | | 2.17±3.18 | | |
|
3 | | 5.53±4.66 | | |
Correlations between clinical characteristics and
clozapine therapy parameters are shown in Table III. A higher daily dose of
clozapine was significantly correlated with higher plasma clozapine
and norclozapine concentrations (ρ=0.515, P<0.001; ρ=0.647,
P<0.001, respectively). Additionally, clozapine and norclozapine
concentrations were strongly positively correlated (ρ=0.850,
P<0.0005).
| Table IIICorrelation of clinical
characteristics and profile of clozapine therapy in patients with
treatment-resistant schizophrenia. |
Table III
Correlation of clinical
characteristics and profile of clozapine therapy in patients with
treatment-resistant schizophrenia.
| Variables | Daily dose of
clozapine (mg/d) | Clozapine
concentration (ng/ml) | Norclozapine
concentration (ng/ml) |
|---|
| GASS-C | ρ=0.137
P=0.382 | ρ=0.098
P=0.554 | ρ=0.133
P=0.420 |
| WHODAS | ρ=0.409
P=0.006 | ρ=0.333
P=0.038 | ρ=0.481
P=0.002 |
| CGI-S | ρ=0.368
P=0.015 | ρ=0.202
P=0.218 | ρ=0.236
P=0.148 |
| GAF | ρ=0.249
P=0.108 | ρ=-0.354
P=0.027 | ρ=-0.370
P=0.020 |
| SNAPSI | ρ=0.209
P=0.508 | ρ=0.198
P=0.538 | ρ=0.346
P=0.271 |
Multiple linear regression analysis identified that
clozapine dose, clozapine concentration, BMI, SNAPSI scores and
CGI-S scores are significantly associated with clozapine side
effects (GASS-C). Norclozapine dose, BMI and CGI-S are
significantly associated with disability (WHODAS).
The following model is given in Table IV. GASS-C=8.245-0.005·(Clozapine
dose) + 0.010·(Clozapine concentration) -0.397·BMI + 0.769·SNAPSI
-2.130·(CGI-S). Wilcoxon signed ranks test indicated no significant
difference between observed and predicted GASS-C scores (P=0.441).
The following model is also provided in Table IV. WHODAS=-16.963 + 0.027·
(Norclozapine concentration) -0.652·BMI + 8.864·(CGI-S). No
significant difference was found between observed and predicted
WHODAS scores (P=0.837).
| Table IVResults of multiple linear regression
analysis, where clozapine-related adverse effects and disability in
patients with treatment-resistant schizophrenia are dependent
variables. |
Table IV
Results of multiple linear regression
analysis, where clozapine-related adverse effects and disability in
patients with treatment-resistant schizophrenia are dependent
variables.
| A, Dependent
variable GASS-C | B | P-value |
|---|
| Constant | 8.245 | |
| Clozapine dose
(mg/d) | -0.005 | 0.045 |
| Clozapine
concentration (ng/ml) | 0.010 | 0.009 |
| BMI
(kg/m2) | -0.397 | 0.010 |
| SNAPSI | 0.769 | 0.012 |
| CGI-S | -2.130 | 0.047 |
| B, Dependent
variable WHODAS | B | P-value |
| Constant | -16.963 | |
| Norclozapine
concentration (ng/ml) | 0.027 | 0.018 |
| BMI
(kg/m2) | -0.652 | 0.013 |
| CGI-S | 8.864 | <0.0005 |
Discussion
The present data indicated that female patients
experience more clozapine adverse effects than males, and that
lower BMI is associated with more side effects. Additionally,
patients with fewer hospitalizations and higher disability (WHODAS
scores) tend to report more side effects. Clozapine dose, plasma
clozapine concentration, BMI, symptom severity (SNAPSI) and illness
severity (CGI-S) were significantly associated with adverse
effects, while norclozapine concentration, BMI and CGI-S were
significantly associated with disability.
Despite the efficacy of clozapine in TRS and its
role in suicide prevention among patients with schizophrenia, its
use remains limited, with only 5-20% of eligible patients receiving
clozapine therapy or continuing treatment in the long term
(40-46).
One possible explanation for this underutilization is the
occurrence of adverse effects (for example, agranulocytosis and
metabolic side effects), which negatively affect treatment
adherence. Therefore, effective treatment strategies are necessary
to facilitate long-term clozapine tolerance and improve its
utilization patterns (47,48).
The patient sample in the present study aligns with
the profile of patients with TRS commonly described in the
literature, predominantly middle-aged males, often smokers, with
low educational attainment and long illness duration (49-51).
The observed male predominance in our cohort (3:1) is specific to
the SBPB Kovin institutional population and may not reflect broader
population trends in TRS. Nonetheless, a recent meta-analysis
indicates that men are more likely than women to develop TRS (OR ≈
1.57) (39). Sex differences could
influence metabolic profiles, side-effect susceptibility, and
smoking patterns, which are important factors to consider when
interpreting drug concentrations and clinical outcomes (1,7-10).
Obesity and increased BMI are among the most
frequently studied adverse effects of clozapine treatment (52,53).
Some authors suggest that unhealthy dietary habits and low levels
of physical activity, commonly observed among patients with
schizophrenia, may also contribute to obesity (53,54).
Furthermore, previous studies indicate that, compared with men,
women on clozapine therapy tend to have higher BMI and glucose
levels, a greater prevalence of triglyceride and LDL cholesterol
dysregulation, and lower blood pressure values (55). These differences may be explained by
findings showing that plasma concentrations of clozapine are
generally higher in women than in men (56,57).
Accordingly, the results of the present study also demonstrated
that women report adverse effects more frequently than men
(56).
Patients who were hospitalized for the first time
reported more adverse effects, likely reflecting the initial
adaptation to treatment. This finding is consistent with previous
observations suggesting that adverse effects may decrease with
continued treatment, thereby improving adherence (58).
The relationship between plasma clozapine levels and
adverse effects is complex. The present study did not find a direct
correlation between clozapine dose or plasma levels and adverse
effects; however, multivariate regression analysis showed that both
dose and plasma concentration were significantly associated when
combined with other factors such as BMI and symptom severity. This
highlights the individual variability in sensitivity to adverse
effects within the therapeutic range. In the present study, higher
disability levels (measured by WHODAS) were correlated with higher
GASS scores, indicating more severe adverse effects. Similar
findings have been reported in previous research. For example, a
study by Gurcan et al (16),
which assessed clozapine-related adverse effects, found a
statistically significant correlation between the severity of
adverse effects and increased levels of disability as measured by
WHODAS (16). Greater disability
(WHODAS) was associated with more severe adverse effects and
illness severity (CGI-S), confirming that both contribute to the
overall disability burden in TRS.
Additionally, norclozapine levels were also
significantly associated with disability, supporting existing
evidence that plasma norclozapine concentrations are associated
with metabolic adverse effects that influence functionality.
Although the exact mechanisms remain unclear, most studies show a
stronger correlation between serum norclozapine levels and
metabolic syndrome parameters than with serum clozapine levels
(59-62).
Previous research also suggests a strong
relationship between illness severity and disability, with illness
severity serving as a predictor of disability level (63). An Indian study investigating the
long-term impact of clozapine on disability and disease course,
among patients treated with clozapine for an average of 5 years,
found that higher CGI-S scores at follow-up, lower global
improvement (CGI-I), and poorer efficacy index (CGI-E) were
associated with greater disability (64). These findings are consistent with
the current results, which also indicate that CGI-S scores have
significantly association with disability. In addition to metabolic
and environmental factors, genetic variability, including
polymorphisms in enzymes such as CYP1A2 and CYP2D6, can
significantly influence clozapine and norclozapine levels as well
as treatment response (8-10,65).
Another important aspect not addressed in the present study
involves pharmacodynamic factors. Receptor characteristics and
pharmacodynamic biomarkers may provide deeper insights into
therapeutic response and will be included, together with genetic
analyses, in the next phase of our multicentric research project
(4,8,10,43).
These results complement findings from the broader multicentric
CLOSER study, which included diagnostically heterogeneous patients
recruited across three centers. By focusing on a localized and
diagnostically homogeneous cohort, the present study allows for a
more detailed evaluation of interindividual variability in
clozapine and norclozapine levels and associated clinical outcomes.
This center-specific analysis contributes nuanced information that
may be masked in larger heterogeneous samples.
The strength of the present study lies in its
provision of real-world data on clozapine levels, effects,
functioning, and side effects during titration in patients with
schizophrenia. Relatively detailed clinical data were collected on
patients treated with clozapine, and clinical outcomes were
assessed using well-established and validated instruments.
However, the study has several limitations. First,
the relatively small sample size is a limitation, even though
validated and widely used instruments were employed, and clinicians
were either trained in their use or had prior experience with them.
The male predominance in our sample reflects both the institutional
population and meta-analytic evidence that men are more likely to
develop TRS (39), which should be
considered when interpreting outcomes. Second, GASS-C is considered
the gold standard for this purpose, it primarily measures the
subjective burden of side effects as experienced by patients, which
may not always align with objectively measurable or clinically
verifiable adverse events. Third, although multivariate linear
regression was used to identify independent predictors of
psychiatrists' attitudes, the cross-sectional nature of the study
prevents causal inferences between variables.
Acknowledgements
The authors would like to thank Mr Dejan Perovanovic
for editing the language and Dr Zvezdana Stojanovic for valuable
suggestions on the analysis.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contribution
VP, DIR and DC conceived and designed the study. VP
and DIR collected the material and data. VP, DIR, DC, BR and DB
performed the data analysis. VP drafted the first version of the
manuscript. All authors revised the manuscript critically for
important intellectual content, commented on previous versions of
the manuscript, read and approved the final version of the
manuscript. All authors agree to be accountable for all aspects of
the work and confirm the authenticity of all the raw data.
Ethics approval and consent to
participate
The present study was approved by the Ethics
Committee of the SBPB Kovin (approval no. 01-3615/3-3659/1; dated
29.11.2017; Kovin, Serbia). Before being included in the study, the
patients signed a consent form for participation in the study, in
accordance with the current Good Clinical Practice (GCP)
regulations.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
References
|
1
|
Elkis H and Buckley PF:
Treatment-resistant schizophrenia. Psychiatr Clin North Am.
39:239–265. 2016.PubMed/NCBI View Article : Google Scholar
|
|
2
|
Demjaha A, Lappin JM, Stahl D, Patel MX,
MacCabe JH, Howes OD, Heslin M, Reininghaus UA, Donoghue K, Lomas
B, et al: Antipsychotic treatment resistance in first-episode
psychosis: Prevalence, subtypes and predictors. Psychol Med.
47:1981–1989. 2017.PubMed/NCBI View Article : Google Scholar
|
|
3
|
Lehman AF, Lieberman JA, Dixon LB,
McGlashan TH, Miller AL, Perkins DO and Kreyenbuhl J: American
Psychiatric Association; Steering Committee on Practice Guidelines.
American psychiatric association and steering committee on practice
guidelines. practice guideline for the treatment of patients with
schizophrenia, second edition. Am J Psychiatry. 161 (Suppl
2):S1–S56. 2004.PubMed/NCBI
|
|
4
|
Taylor DM: Clozapine for
treatment-resistant schizophrenia: Still the gold standard? CNS
Drugs. 31:177–180. 2017.PubMed/NCBI View Article : Google Scholar
|
|
5
|
Cohen D: Prescribers fear as a major
side-effect of clozapine. Acta Psychiatr Scand. 130:154–159.
2014.PubMed/NCBI View Article : Google Scholar
|
|
6
|
Verdoux H, Bittner RA, Hasan A, Qubad M,
Wagner E, Lepetit A, Romero MA, Bachmann C, Beex-Oosterhuis M,
Bogers J, et al: The time has come for revising the rules of
clozapine blood monitoring in Europe. A joint expert statement from
the European clozapine task force. Eur Psychiatry.
68(e17)2025.PubMed/NCBI View Article : Google Scholar
|
|
7
|
De Leon J, Armstrong SC and Cozza KL: The
dosing of atypical antipsychotics. Psychosomatics. 46:262–73.
2005.PubMed/NCBI View Article : Google Scholar
|
|
8
|
Mach A, Wnorowska A, Siwek M, Wojnar M and
Radziwoń-Zaleska M: Clinical and pharmacological factors
influencing serum clozapine and norclozapine levels. Front
Pharmacol. 15(1356813)2024.PubMed/NCBI View Article : Google Scholar
|
|
9
|
Tralongo F, Konecki C, Feliu C, Kaladjian
A and Djerada Z: Association between clozapine plasma
concentrations and treatment response: A systematic review,
meta-analysis and individual participant data meta-analysis. Clin
Pharmacokinet. 62:807–818. 2023.PubMed/NCBI View Article : Google Scholar
|
|
10
|
Nomura N, Kitagawa K, So R, Misawa F,
Kodama M, Takeuchi H, Bies R, Straubinger T..Banker C, Mizuno Y, et
al: Comprehensive assessment of exposure to clozapine in
association with side effects among patients with
treatment-resistant schizophrenia: A population pharmacokinetic
study. Ther Adv Psychopharmacol.
11(20451253211016189)2021.PubMed/NCBI View Article : Google Scholar
|
|
11
|
de Haas HJ, Cohen D, de Koning MB, van
Weringh G, Petrovic V, de Haan L, Touw DJ and Ignjatovic Ristic D:
Clozapine levels and outcomes in Serbian patients with
treatment-resistant psychotic disorders previously treated without
measuring clozapine levels (CLOSER). Psychiatry Res.
339(116070)2024.PubMed/NCBI View Article : Google Scholar
|
|
12
|
Hynes C, Keating D, McWilliams S, Madigan
K, Kinsella A, Maidment I, Feetam C, Drake RJ, Haddad PM, Gaughran
F, et al: Glasgow antipsychotic sideeffects scale for
clozapine-development and validation of a clozapine-specific
side-effects scale. Schizophr Res. 168:505–513. 2015.PubMed/NCBI View Article : Google Scholar
|
|
13
|
Seppälä N, Leinonen E, Viikki M, Solismaa
A, Nuolivirta T and Kampman O: Factors associated with subjective
side-effects during clozapine treatment. Nord J Psychiatry.
69:161–166. 2015.PubMed/NCBI View Article : Google Scholar
|
|
14
|
Yusufi B, Mukherjee S, Flanagan R, Paton
C, Dunn G, Page E and Barnes TR: Prevalence and nature of
side-effects during clozapine maintenance treatment and the
relationship with clozapine dose and plasma concentration. Int Clin
Psychopharmacol. 22:238–243. 2007.PubMed/NCBI View Article : Google Scholar
|
|
15
|
Naber D, Moritz S, Lambert M, Pajonk GF,
Holzbach R, Mass R and Andresen B: Improvement of schizophrenic
patients' subjective well-being under atypical antipsychotic drugs.
Schizophr Res. 30: 50:79–88. 2001.PubMed/NCBI View Article : Google Scholar
|
|
16
|
Gürcan G, Hun Şenol Ş, Anıl Yağcıoğlu AE,
Karahan S and Ertuğrul A: Common side effects and metabolic
syndrome due to clozapine: Relationship with the clinical variables
and disability. Turk Psikiyatri Derg. 32:87–99. 2021.PubMed/NCBI View
Article : Google Scholar : (In English,
Turkish).
|
|
17
|
Charlson FJ, Ferrari AJ, Santomauro DF,
Diminic S, Stockings E, Scott JG, McGrath JJ and Whiteford HA:
Global epidemiology and burden of schizophrenia: Findings from the
global burden of disease study 2016. Schizophr Bull. 44:1195–1203.
2018.PubMed/NCBI View Article : Google Scholar
|
|
18
|
Taylor D, Paton C and Kapur S: Maudsley
Prescribing Guidelines in Psychiatry. 12th Edition.
Wiley-Blackwell, Oxford, 165-85, 2015.
|
|
19
|
Bleakley S and Taylor D: The Clozapine
Handbook. 1st Edition. Lloyd-Reinhold Communications LLP,
Warwickshire, pp36-119, 2013.
|
|
20
|
De Berardis D, Rapini G, Olivieri L, Di
Nicola D, Tomasetti C, Valchera A, Fornaro M, Di Fabio F, Perna G,
Di Nicola M, et al: Safety of antipsychotics for the treatment of
schizophrenia: A focus on the adverse effects of clozapine. Ther
Adv Drug Saf. 9:237–256. 2018.PubMed/NCBI View Article : Google Scholar
|
|
21
|
Ignjatović Ristić D, Cohen D, Obradović A,
Nikić-Đuričić K, Drašković M and Hinić D: The Glasgow antipsychotic
side-effects scale for clozapine in inpatients and outpatients with
schizophrenia or schizoaffective disorder. Nord J Psychiatry.
72:124–129. 2018.PubMed/NCBI View Article : Google Scholar
|
|
22
|
World Health Organization (WHO). World
Report on Disability 2011. https://www.who.int/disabilities/world_report/2011/report.
|
|
23
|
Zipursky RB, Reilly TJ and Murray RM: The
myth of schizophrenia as a progressive brain disease. Schizophr
Bull. 39:1363–1372. 2013.PubMed/NCBI View Article : Google Scholar
|
|
24
|
Cheniaux E, Landeira-Fernandez J, Lessa
Telles L, Lessa JL, Dias A, Duncan T and Versiani M: Does
schizoaffective disorder really exist? A systematic review of the
studies that compared schizoaffective disorder with schizophrenia
or mood disorders. J Affect Disord. 106:209–217. 2008.PubMed/NCBI View Article : Google Scholar
|
|
25
|
Rey Souto D, Pinzón Espinosa J, Vieta E
and Benabarre Hernández A: Clozapine in patients with
schizoaffective disorder: A systematic review. Rev Psiquiatr Salud
Ment (Engl Ed). 14:148–156. 2021.PubMed/NCBI View Article : Google Scholar
|
|
26
|
Correll CU and Howes OD:
Treatment-resistant schizophrenia: Definitions, predictors, and
therapy options. J Clin Psychiatry. 82(MY20096AH1C)2021.PubMed/NCBI View Article : Google Scholar
|
|
27
|
Chopra PK, Couper JW and Herrman H: The
assessment of patients with long-term psychotic disorders:
Application of the WHO Disability Assessment Schedule II. Aust N Z
J Psychiatry. 38:753–759. 2004.PubMed/NCBI View Article : Google Scholar
|
|
28
|
Holmberg C, Gremyr A, Torgerson J and
Mehlig K: Clinical validity of the 12-item. WHODAS-2.0 in a
naturalistic sample of outpatients with psychotic disorders. BMC
Psychiatry. 21(147)2021.PubMed/NCBI View Article : Google Scholar
|
|
29
|
Leucht S, Kane JM, Etschel E, Kissling W,
Hamann J and Engel RR: Linking the PANSS, BPRS, and CGI: Clinical
implications. Neuropsychopharmacology. 31:2318–2325.
2006.PubMed/NCBI View Article : Google Scholar
|
|
30
|
American Psychiatric Association:
Diagnostic and Statistical Manual of Mental Disorders. 4th Edition.
American Psychiatric Association, Washington, DC, 2000.
|
|
31
|
Startup M, Jackson MC and Bendix S: The
concurrent validity of the Global assessment of functioning (GAF).
Br J Clin Psychol. 41 (Pt 4):417–l422. 2002.PubMed/NCBI View Article : Google Scholar
|
|
32
|
Kirkpatrick B, Strauss GP, Nguyen L,
Fischer BA, Daniel DG, Cienfuegos A and Marder SR: The brief
negative symptom scale: Psychometric properties. Schizophr Bull.
37:300–305. 2011.PubMed/NCBI View Article : Google Scholar
|
|
33
|
Østergaard SD, Lemming OM, Mors O, Correll
CU and Bech P: PANSS-6: A brief rating scale for the measurement of
severity in schizophrenia. Acta Psychiatr Scand. 133:436–444.
2016.PubMed/NCBI View Article : Google Scholar
|
|
34
|
Østergaard SD, Foldager L, Mors O, Bech P
and Correll CU: The validity and sensitivity of PANSS-6 in the
clinical antipsychotic trials of intervention effectiveness (CATIE)
study. Schizophr Bull. 44:453–462. 2018.PubMed/NCBI View Article : Google Scholar
|
|
35
|
Nielsen CM, Kølbæk P, Dines D, Pedersen
ML, Danielsen AA, Holmgård C, Wissing S, Esbøl AM, Fuglsang NFB,
Nguyen TD, et al: Validation of ratings on the six-item positive
and negative syndrome scale obtained via the simplified negative
and positive symptoms interview among outpatients with
schizophrenia. J Psychopharmacol. 36:1208–1217. 2022.PubMed/NCBI View Article : Google Scholar
|
|
36
|
Geers LM, Loonen AJM and Touw DJ:
Microsampling techniques suitable for therapeutic drug monitoring
of antipsychotics. J Clin Psychopharmacol. 44:302–310.
2024.PubMed/NCBI View Article : Google Scholar
|
|
37
|
Geers LM, Cohen D, Wehkamp LM, van Hateren
K, Koster RA, Fedorenko OY, Semke AV, Bokhan N, Ivanova SA,
Kosterink JGW, et al: Dried blood spot analysis for therapeutic
drug monitoring of clozapine. J Clin Psychiatry. 78:e1211–e1218.
2017.PubMed/NCBI View Article : Google Scholar
|
|
38
|
Geers LM, Cohen D, Wehkamp LM, van Wattum
HJ, Kosterink JGW, Loonen AJM and Touw DJ: Population
pharmacokinetic model and limited sampling strategy for clozapine
using plasma and dried blood spot samples. Ther Adv
Psychopharmacol. 12(20451253211065857)2022.PubMed/NCBI View Article : Google Scholar
|
|
39
|
Siskind D, Orr S2, Sinha S, Yu O, Brijball
B, Warren N, MacCabe JH, Smart SE and Kisely S: Rates of
treatment-resistant schizophrenia from first-episode cohorts:
Systematic review and meta-analysis. Br J Psychiatry. 220:115–120.
2022.PubMed/NCBI View Article : Google Scholar
|
|
40
|
Verdoux H, Quiles C, Bachmann CJ and
Siskind D: Prescriber and institutional barriers and facilitators
of clozapine use: A systematic review. Schizophr Res. 201:10–19.
2018.PubMed/NCBI View Article : Google Scholar
|
|
41
|
Warnez S and Alessi-Severini S: Clozapine:
A review of clinical practice guidelines and prescribing trends.
BMC Psychiatry. 14(102)2014.PubMed/NCBI View Article : Google Scholar
|
|
42
|
Zalsman G, Hawton K, Wasserman D, van
Heeringen K, Arensman E, Sarchiapone M, Carli V, Höschl C, Barzilay
R, Balazs J, et al: Suicide prevention strategies revisited:
10-year systematic review. Lancet Psychiatry. 3:646–659.
2016.PubMed/NCBI View Article : Google Scholar
|
|
43
|
Khokhar JY, Henricks AM, Sullivan EDK and
Green AI: Unique effects of clozapine: A pharmacological
perspective. Adv Pharmacol. 82:137–162. 2018.PubMed/NCBI View Article : Google Scholar
|
|
44
|
Olfson M, Gerhard T, Crystal S and Stroup
TS: Clozapine for schizophrenia: State variation in evidence-based
practice. Psychiatr Serv. 67(152)2016.PubMed/NCBI View Article : Google Scholar
|
|
45
|
Okhuijsen-Pfeifer C, Cohen D, Bogers JPAM,
de Vos CMH, Huijsman EAH, Kahn RS and Luykx JJ: Differences between
physicians' and nurse practitioners' viewpoints on reasons for
clozapine underprescription. Brain Behav. 9(e01318)2019.PubMed/NCBI View Article : Google Scholar
|
|
46
|
Rubio JM and Kane JM: How and when to use
clozapine. Acta Psychiatr Scand. 141:178–189. 2020.PubMed/NCBI View Article : Google Scholar
|
|
47
|
De Fazio P, Gaetano R, Caroleo M,
Cerminara G, Maida F, Bruno A, Muscatello MR, Moreno MJ, Russo E
and Segura-García C: Rare and very rare adverse effects of
clozapine. Neuropsychiatr Dis Treat. 11:1995–2003. 2015.PubMed/NCBI View Article : Google Scholar
|
|
48
|
Smith RC, Leucht S and Davis JM:
Maximizing response to first-line antipsychotics in schizophrenia:
A review focused on finding from meta-analysis. Psychopharmacology
(Berl). 236:545–559. 2019.PubMed/NCBI View Article : Google Scholar
|
|
49
|
Kelly DL, McMahon RP, Liu F, Love RC,
Wehring HJ, Shim JC, Warren KR and Conley RR: Cardiovascular
disease mortality in patients with chronic schizophrenia treated
with clozapine: A retrospective cohort study. J Clin Psychiatry.
71:304–311. 2010.PubMed/NCBI View Article : Google Scholar
|
|
50
|
Jönsson L, Simonsen J, Brain C, Kymes S
and Watson L: Identifying and characterizing treatment-resistant
schizophrenia in observational database studies. Int J Methods
Psychiatr Res. 28(e1778)2019.PubMed/NCBI View Article : Google Scholar
|
|
51
|
Correll CU, Brevig T and Brain C:
Exploration of treatment-resistant schizophrenia subtypes based on
a survey of 204 US psychiatrists. Neuropsychiatr Dis Treat.
15:3461–3473. 2019.PubMed/NCBI View Article : Google Scholar
|
|
52
|
Marinkovic D, Timotijevic I, Babinski T,
Totic S and Paunovic VR: The side-effects of clozapine: A four year
follow-up study. Prog Neuropsychopharmacol Biol Psychiatry.
18:537–544. 1994.PubMed/NCBI View Article : Google Scholar
|
|
53
|
Henderson DC, Fan X, Copeland PM, Borba
CP, Daley TB, Nguyen DD, Zhang H, Hayden D, Freudenreich O, Cather
C, et al: A double-blind, placebo-controlled trial of sibutramine
for clozapine-associated weight gain. Acta PsychiatrScand.
115:101–105. 2007.PubMed/NCBI View Article : Google Scholar
|
|
54
|
Heald A, Livingston M, Yung A and De Hert
MA: Prescribing in schizophrenia and psychosis: Increasing
polypharmacy over time. Hum Psychopharmacol. 32:2017.PubMed/NCBI View Article : Google Scholar
|
|
55
|
Correll CU, Brevig T and Brain C: Patient
characteristics, burden and pharmacotherapy of treatment-resistant
schizophrenia: Results from a survey of 204 US psychiatrists. BMC
Psychiatry. 19(362)2019.PubMed/NCBI View Article : Google Scholar
|
|
56
|
Martini F, Spangaro M, Buonocore M, Bechi
M, Cocchi F, Guglielmino C, Bianchi L, Sapienza J, Agostoni G,
Mastromatteo A, et al: Clozapine tolerability in treatment
resistant schizophrenia: Exploring the role of sex. Psychiatry Res.
297(113698)2021.PubMed/NCBI View Article : Google Scholar
|
|
57
|
Moreno-Küstner B, Martín C and Pastor L:
Prevalence of psychotic disorders and its association with
methodological issues. A systematic review and meta-analyses. PLoS
One. 13(e0195687)2018.PubMed/NCBI View Article : Google Scholar
|
|
58
|
Procyshyn RM, Vila-Rodriguez F, Honer WG
and Barr AM: Clozapine administered once versus twice daily: Does
it make a difference? Med Hypotheses. 82:225–228. 2014.PubMed/NCBI View Article : Google Scholar
|
|
59
|
McKibbin C, Patterson TL and Jeste DV:
Assessing disability in older patients with schizophrenia: Results
from the WHODAS-II. J NervMent Dis. 192:405–413. 2004.PubMed/NCBI View Article : Google Scholar
|
|
60
|
Lu ML, Lane HY, Lin SK, Chen KP and Chang
WH: Adjunctive fluvoxamine inhibits clozapine-related weight gain
and metabolic disturbances. J Clin Psychiatry. 65:766–771.
2004.PubMed/NCBI View Article : Google Scholar
|
|
61
|
Lau SL, Muir C, Assur Y, Beach R, Tran B,
Bartrop R, McLean M and Caetano D: Predicting weight gain in
patients treated with clozapine: The role of sex, body mass index,
and smoking. J Clin Psychopharmacol. 36:120–124. 2016.PubMed/NCBI View Article : Google Scholar
|
|
62
|
Jessurun NT, Derijks HJ, van Marum J,
Jongkind A, Giraud LE, van Puijenbroek P and Grootens KP: Body
weight gain in clozapine-treated patients: Is norclozapine the
culprit? Br J Clin Pharmacol. 88:853–857. 2022.PubMed/NCBI View Article : Google Scholar
|
|
63
|
Ertuğrul A and Uluğ B: The influence of
neurocognitive deficits and symptoms on disability in
schizophrenia. Acta PsychiatrScand. 105:196–201. 2002.PubMed/NCBI View Article : Google Scholar
|
|
64
|
Grover S, Naskar C and Chakrabarti S:
Impact of clozapine on disability and course of illness in patients
with schizophrenia: A study from North India. Indian J Psychiatry.
63:588–592. 2021.PubMed/NCBI View Article : Google Scholar
|
|
65
|
Kappel DB, Rees E, Fenner E, King A,
Jansen J, Helthuis M, Owen MJ, O'Donovan MC, Walters JTR and
Pardiñas AF: Rare variants in pharmacogenes influence clozapine
metabolism in individuals with schizophrenia. Eur
Neuropsychopharmacol. 80:47–54. 2024.PubMed/NCBI View Article : Google Scholar
|
