|Year : 2022 | Volume
| Issue : 2 | Page : 119-125
Comparative effects of clozapine and risperidone monotherapy on levels of immunoglobulins in patients with schizophrenia – A 12 weeks' longitudinal study
Sumeesha Jaswal1, Ajeet Sidana1, Shivangi Mehta1, Seema Gupta2, Gurjit Kaur3
1 Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
2 Department of Biochemistry, Government Medical College and Hospital, Chandigarh, India
3 Department of Physiology, Government Medical College and Hospital, Chandigarh, India
|Date of Submission||29-Jan-2022|
|Date of Decision||16-Apr-2022|
|Date of Acceptance||14-May-2022|
|Date of Web Publication||13-Jan-2023|
Dr. Sumeesha Jaswal
Department of Psychiatry, Government Medical College and Hospital, Chandigarh
Source of Support: None, Conflict of Interest: None
Background: Schizophrenia is among the most puzzling yet disabling of all brain diseases. The finding of immunity-related genes seems to vindicate theories about the involvement of neuroimmunological processes in the pathogenesis of schizophrenia. Moreover, antipsychotics used in the treatment of schizophrenia have been shown to have effects on serum immunoglobulin levels. Aim: The aim of this study was to assess and compare the effect of risperidone and clozapine on the immunoglobulins at 6 weeks and 12 weeks in patients with schizophrenia and its clinical correlation. Materials and Methods: It was an open-label, randomized, comparative, and prospective study. Patients with International Classification of Diseases-11th Revision diagnosis of schizophrenia who were not on any antipsychotic drug for more than 2 weeks, were randomized to two groups, i.e., A (risperidone) and B (clozapine) after baseline assessment of sociodemographic and clinical parameters on the Positive and Negative Syndrome Scale (PANSS). Baseline blood investigations (complete hemogram, liver and renal function tests, lipid profile, and fasting blood sugar) and immunoglobulin estimation were done. Patients were followed at 6 weeks and 12 weeks and levels of immunoglobulin were reassessed at 6 weeks and 12 weeks along with PANSS and Glasgow Antipsychotic Side-Effect checklist. Results: A total of 32 patients were inducted into the study – 16 in the risperidone group and 16 in the clozapine group. There was no statistically significant difference in terms of the duration of illness or period of exacerbation between the two groups though the baseline total PANSS score was significantly higher in the clozapine group. In both the groups, there was no statistically significant difference in the baseline immunoglobulin levels at baseline and over 12 weeks in terms of the immunoglobulin G (IgG), IgM, and IgE levels. Within the clozapine group, a significant difference over 12 weeks was noted in IgG level. Conclusion: It can be concluded from the index study that the immunoglobulin levels in the patients with schizophrenia do not differ much concerning the effect of risperidone and clozapine. Clozapine is associated with a significant increase in IgG levels indicating the immunologic response of clozapine in schizophrenia.
Keywords: Clozapine, immunoglobulins, risperidone, schizophrenia
|How to cite this article:|
Jaswal S, Sidana A, Mehta S, Gupta S, Kaur G. Comparative effects of clozapine and risperidone monotherapy on levels of immunoglobulins in patients with schizophrenia – A 12 weeks' longitudinal study. J Mental Health Hum Behav 2022;27:119-25
|How to cite this URL:|
Jaswal S, Sidana A, Mehta S, Gupta S, Kaur G. Comparative effects of clozapine and risperidone monotherapy on levels of immunoglobulins in patients with schizophrenia – A 12 weeks' longitudinal study. J Mental Health Hum Behav [serial online] 2022 [cited 2023 Mar 31];27:119-25. Available from: https://www.jmhhb.org/text.asp?2022/27/2/119/367738
| Introduction|| |
Schizophrenia is among the most puzzling yet disabling of all brain diseases, characterized by distortions in thinking and perception and inappropriate or blunt affect leading to functional disruption. Recent genome-wide association studies converge on genes involved in the regulation of synaptic activities, neurodevelopment, and immune functions for the etiopathogenesis of schizophrenia. The finding of immunity-related genes seems to vindicate theories about the involvement of neuroimmunological processes in the pathogenesis of schizophrenia. It has been hypothesized that psychopathological symptoms and inflammation are associated with the immune stress response, and inflammation is also involved in stress-related changes in behavior induced by cytokines and mediated by neurotransmitters. Thus, schizophrenia has been described to be associated with chronic inflammation in the central nervous system. Considering the immunological involvement in schizophrenia, various studies have been conducted that measured interleukins and immunoglobulins to further elucidate the pathophysiology in schizophrenia.
The studies on serum immunoglobulins in patients with schizophrenia have shown inconsistent and nonspecific changes with a lack of concordance among various reports. Tiwari et al. found increased levels of serum and cerebrospinal fluid immunoglobulins (IgA and IgM), whereas Narasimha Rao et al. observed no significant differences in immunoglobulin levels between schizophrenia (paranoid and nonparanoid) patients and normal controls. Moreover, antipsychotics used in the treatment of schizophrenia have been shown to have effects on serum immunoglobulin levels. There have been case reports which reported hypogammaglobulinemia with significant fall in IgM, IgA, and IgG in patients on haloperidol, chlorpromazine, and levomepromazine.
Among the atypical antipsychotics, a singular study on the effect of risperidone on in vitro polyclonal IgG and IgM synthesis by human peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed mitogen (PWM) showed that risperidone decreased IgG synthesis in PBMC of healthy controls only at the high concentration and IgG synthesis enhanced by serotonin was antagonized by risperidone, but this effect, however, was not statistically significant. Risperidone did not affect IgM synthesis. Risperidone did not affect the production of IgG and IgM by PBMC of schizophrenic subjects in PWM-stimulated cultures both before and after risperidone therapy.
Another commonly prescribed atypical antipsychotic, clozapine as such, has very limited literature studying its effect on immunoglobulin levels. A case–control study was conducted that investigated selective immunoglobulin M deficiency among clozapine-treated patients. The results showed IgM deficiency in 14% of clozapine-treated patients. The possible mechanism was clozapine dysregulating cytokines – both type 1 (subchronic treatment with clozapine increasing soluble interleukin [IL-2] R levels) and type 2 (e.g., IL-10 and IL-6).
A case–control study carried out by Ponsford et al. aimed to evaluate the association between clozapine and antibody deficiency in patients with schizophrenia. It found a significant reduction in immunoglobulin levels in patients treated with clozapine (n = 123) compared with those who were clozapine naive (n = 111). The study noted an immediate decrease in IgA and IgM and a significant association between decline in immunoglobulins and clozapine duration. A significant negative correlation between the duration of clozapine use and an annual reduction in IgG level of 0.15 g/L was also observed.
In another 6-week longitudinal study, the effect of clozapine treatment and effect on in vitro PBMC cultures were studied. In this systematic longitudinal investigation of in vitro immune parameters and autoantibody patterns in clozapine-treated patients, clozapine treatment did not induce a panel of common autoantibodies in patients in 6 weeks, in particular, it did not induce autoantibodies against thromboplastin, which had been reported in a patient with clozapine-associated coagulopathy. Concerning humoral aspects of immunity, they found that IgG serum levels, but not IgM or IgA serum levels, were significantly elevated at the end of week 6.
The available research on the effect of treatment on levels of immunoglobulins in patients with schizophrenia is inconsistent. Moreover, the authors could not find any head-to-head trial of risperidone and clozapine for comparison of the effect on immunoglobulins in schizophrenia. The study hypothesized minimal changes in immunoglobulin level in patients treated with risperidone and a decreasing trend in the immunoglobulin levels in patients treated with clozapine, considering the available literature. There is no Indian study in a similar area. Hence, it was planned to see the baseline Ig levels in schizophrenia and compare the effect of risperidone and clozapine on Ig levels over 12 weeks in relation to clinical parameters.
| Materials and Methods|| |
The study was undertaken at the Department of Psychiatry of a tertiary care teaching hospital in northern India. The department of psychiatry runs a daily walk-in clinic for the patients coming to the outpatient department (OPD) for the first time. The researcher enrolled the patients with the diagnosis of schizophrenia according to the International Classification of Diseases-11th Revision visiting the OPD for the first time. In addition, these patients were required to be not on any antipsychotic drug for more than 2 weeks (patients on treatment were given a washout period of 7 days if unresponsive to the antipsychotic), in the age range of 18–45 years, and willing to give written informed consent for participation in the study. For patients who lacked capacity, informed consent was obtained from the nominated representative.
Patients on immunosuppressants; with overt infection in the past 2 weeks, hematological disorders, chronic liver or kidney disease, autoimmune disorders, and chronic inflammatory disease; on antibiotics (chloramphenicol, tetracycline, rifampicin, polymyxin B, and nitrofurantoin), with known immunodeficiency disorder; with epilepsy; those unable to tolerate clozapine or risperidone; with agranulocytosis or granulocytopenia; with paralytic ileus, CNS depression, and myeloproliferative disorder; with substance use disorder except tobacco and caffeine, pregnant and lactating women, and those who had received depot antipsychotics in the past 3 months were excluded from the study. Electrocardiogram and various laboratory investigations, including hemogram, renal function tests (RFTs), liver function tests (LFTs), fasting blood sugar (FBS), and metabolic profile, were carried out to screen patients for any undiagnosed medical illness. In addition, patients on clozapine also underwent weekly complete blood count.
The study participants were recruited through consecutive sampling methods from January 2020 to August 2021. A total of 32 participants were included in the study. A final analysis of 32 participants was performed.
Sociodemographic and clinical characteristics of participants were recorded in a semi-structured pro forma developed for the study. The Positive and Negative Syndrome Scale (PANSS) was applied to all the patients before starting the antipsychotic to assess baseline severity. A baseline blood sample of 4 ml was drawn for complete hemogram and biochemical testing (FBS, LFT, RFT, and lipid profile). Another blood sample of 5 ml was taken for immunoglobulin estimation in a plain vial. IgE measurement was done by chemiluminescence method (ADVIA) while IgM, IgA, and IgG measurement was done by immunoturbidimetric method (IMOLA). The coefficient of variance for the method of estimation of all immunoglobulins was <3%. Patients were randomized into two groups – A and B (using a computer-generated random number table). Group A was prescribed risperidone while Group B received clozapine. The dosage of both the molecules was kept in the therapeutic range (clozapine: up to 900 mg/day and risperidone: 2–8 mg/day) and intention-to-treat analysis was used. An initial dose of 2 mg/day for risperidone was started, which was gradually escalated to achieve the maximum tolerable therapeutic doses by the end of 4–6 weeks. For clozapine, Maudsley's prescription guidelines were followed, with a beginning dose of 12.5 mg once a day, which was gradually escalated to achieve the maximum tolerable therapeutic doses by the end of 4–6 weeks. The response was assessed (a ≥50% improvement in the PANSS from baseline to endpoint). Thereafter, participants were continued on the same dose till the completion of the study period, i.e., 12 weeks. Patients were followed at 6 weeks and 12 weeks, and repeat levels of immunoglobulin were assessed at 6 weeks and 12 weeks along with PANSS and Glasgow Antipsychotic Side-Effect (GAS) checklist applied. Initially, it was planned that if in case, any patient develops immunoglobulin deficiency, i.e., IgA <0.5 g/l, IgG <5 g/l, and IgM <0.4 g/l during the study, the patient would be dropped from the study and will be managed with standard protocol in such cases. During the study, none of the patients developed immunoglobulin deficiency and thus were not dropped from the study. Both medicines, i.e., clozapine and risperidone, were dispensed from the hospital dispensary free of cost. The Institutional Ethics Committee approved the study. The confidentiality of patient information was maintained, and principles laid down by the Declaration of Helsinki and the Indian Medical Council of Research were adhered to. The study was registered with the Clinical Trials Registry of India.
The sociodemographic and clinical characteristics of the two groups were compared using independent t-test and Chi-square test for the continuous and categorical variables, respectively. The normality of the variables (quantitative data) was checked with the Shapiro–Wilk test/Kolmogorov–Smirnov test of normality [Supplementary Table 1]. Data that were skewed were expressed in the form of their mean, SD, median, and interquartile range. Group comparison of data was made with the Mann–Whitney test. For time-related variables of data, Wilcoxon signed-rank test was applied. The significance was kept at P < 0.05 and a value of <0.001 as highly significant. All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS for Windows, Version 16.0. Chicago, USA, SPSS Inc.).
| Results|| |
A total of 32 patients were induced in the study – 16 in the risperidone group and 16 in the clozapine group. Eighteen patients were male (56.25%) while 14 patients were female (43.75%). The majority of the patients belonged to the age range of 22–44 years, with a mean of 33.31 years ± 5.85 years.
Both the groups were comparable on sociodemographic profile, and there was no statistical difference.
[Table 1] shows the comparison of the two groups in terms of clinical and biochemical profiles.
The total duration of illness in the risperidone group ranged from 6 months to 20 years (mean of 9.66 years ± 6.8 years). The period of exacerbation of symptoms ranged from 1 to 6 months (mean: 3.31 ± 1.54 months) in the risperidone group.
The total duration of illness in the clozapine group ranged from 2 years to 25 years (mean of 11.56 years ± 7.09 years). The period of exacerbation of symptoms ranged from 2 to 6 months (mean: 3.56 ± 1.46 months) in the clozapine group.
There was no statistically significant difference in terms of the duration of illness or period of exacerbation between the two groups. The baseline neutrophil, lymphocyte, and basophil were significantly higher in the clozapine group.
The total PANSS score was significantly higher in the clozapine group (mean: 57.38 ± 8.75) than the risperidone group (mean: 51.31 ± 6.05) with P = 0.028 with a significant difference in the general psychopathology score (P = 0.007).
There was no statistically significant difference in the baseline immunoglobulin levels in both the groups. At week 6, there was a significant difference in the IgE value in the two groups. The clozapine group had a higher side effect score on GAS. At week 6, the mean dose of risperidone was 4.75 mg ± 1.53 mg/day and clozapine was 331 mg ± 98.53 mg/day.
At week 12, there was a significant difference in the IgA value in the two groups. The difference in the side effect score became nonsignificant at week 12. At week 12, the mean dose of risperidone was 4.75 mg ± 1.34 mg/day and clozapine was 285.94 mg ± 86.59 mg/day. The mean dosage of clozapine had been decreased as well as mean GAS score had also decreased.
There were no significant differences between the two groups over the 12 weeks in terms of the IgG, IgM, and IgE levels [Table 2].
The immunoglobulin profile is shown at baseline, week 6, and week 12 in [Table 3].
Illness profile over 12 weeks in the risperidone and clozapine groups showed a significant fall in all parameters of PANSS, as shown in [Table 4].
The immunoglobulin profile did not show a significant change in the risperidone group over 12 weeks, as shown in [Table 5].
Within the clozapine group, a significant change over 12 weeks though other immunoglobulins did not have any significant change was noted in IgG level, as shown in [Table 5].
| Discussion|| |
The index study was a longitudinal, prospective, randomized study carried out with the aim to compare the effect of risperidone and clozapine on the level of immunoglobulins over 12 weeks in patients with schizophrenia.
There was no statistically significant difference in the two groups in terms of the sociodemographical profile, duration of illness, or period of exacerbation. In the index study, the mean total duration of illness in the clozapine group was 11.56 years ± 7.09 years, while in the risperidone, the mean total duration of illness was 9.66 years ± 6.8 years. Thus, patients might have been exposed to antipsychotics in the past which explains the higher lipid profile in some patients. Both the drugs had significant responses in terms of illness profile. There was a significant increase in the side effects as measured by the GAS effect scale by week 6, which was significantly more in the clozapine group than the risperidone group. By week 12, the mean dosage of clozapine had been decreased as well as the mean GAS score had also decreased. The difference in the side effect score became nonsignificant at week 12.
Baseline immunoglobulins in both the groups were in the normal range, i.e., IgA: 0.9–4.5 g/L, IgM: 0.4–2.3 g/L, and IgG: 7–16 g/L, except for IgE levels which were higher at baseline than normal IgE levels (1.5–144 IU/L) in both the risperidone and clozapine groups. Such findings of baseline immunoglobulin levels have also been seen in another study carried out in serum of 334 psychiatric patients which showed no differences for the IgG and IgA among the groups studied (92 patients with bipolar depression, 150 patients with unipolar depression, and 95 patients with schizophrenia). They had rather found increased levels of IgM in all psychiatric patients in their study. Although literature supports higher levels of IgA, IgM, and IgD,, higher levels of immunoglobulin E have only been cited by Ramchand et al. In their study, Ramchand et al., reported elevated levels of immunoglobulin E in poor responders to neuroleptic treatment. In contrast to it, our study reports higher levels of IgE, but it is not associated with poor response.
In our study, with risperidone treatment, the mean value of IgM, IgG, and IgE further increased while the mean value of IgA level decreased over 12 weeks, but the change was not statistically significant. In vitro studies have shown risperidone to dysregulate innate and adaptive immune responses to the extent of preventing treated animals from mounting an antibody response following vaccination with Pneumovax 23. Global immunosuppression, myeloid dysplasia in the bone marrow, and thymic involution by risperidone, and disruption of mitochondrial function and the cardio-immune axis by risperidone have been reported.,
The above findings have been refuted in our study, with risperidone showing immunopotentiating effect rather than immunosuppression.
Another study reported an increase of serum IgG and also reported unstimulated production of IgG to be significantly increased. Higher unstimulated production of IgG compared with PWM-stimulated production of IgG but not of IgM was observed in a study. After 6-week risperidone therapy, there were significantly decreased IgG levels in the serum of those treated with risperidone. Although the spontaneous production remained increased compared with PWM-stimulated production, it was lower than before the initiation of therapy. After 24 weeks, the levels of serum IgG and IgM were significantly reduced. After long-term therapy, the ratio between unstimulated and PWM-stimulated production of IgG was normalized and the total amount of IgG produced was significantly lower than that before the therapy. The finding in the index study negates the above finding as to the change in immunoglobulin levels in the index study, i.e., increase in IgG levels and decrease in immunoglobulin A levels were not found to be statistically significant. A possible reason for the variance in results can be the different ethnic profiles in both study samples, which has been shown to affect the immunoglobulin levels in patients. Furthermore, the index study is an in vivo study in comparison to the in vitro study mentioned.
In the index study, with clozapine treatment, the mean value of IgA, IgE, and IgG further increased while the mean value of IgM level decreased over 12 weeks, but the change was not significant except a significant difference over 12 weeks was noted in IgG level. Hinze et al., in their longitudinal study, investigated immune parameters such as interleukin-2, interleukin-6, autoantibodies, and IgG, IgA, and IgM concentration. Seventeen patients with schizophrenia were evaluated, and the authors reported no effect on the level of autoantibodies in the serum of the patients over 12 weeks. Clozapine led to an increase in IgG levels at the end of week 6. IgM and IgA showed no such significant effect. The findings of the index study are in concurrence with the same study.
Hypogammaglobulinemia and IgM deficiency have been reported in the literature, but the index study did not find a significant change in the IgM level on treatment with clozapine over 12 weeks.
Ponsford et al. had reported an association between clozapine and antibody deficiency. They found a significant reduction in immunoglobulin levels in patients treated with clozapine with an immediate decrease in IgA and IgM and a significant association between decline in IgG and clozapine duration. Clozapine use has been implicated in increased chances of infection., Individuals who were on clozapine had an increased risk of COVID-19 infection compared with those who were on other antipsychotic medications. Such finding was not corroborated in our study due to different patient populations. Ponsford et al. studied patients that were already on clozapine for a variable period, while our study is prospective.
The level of IgG, as seen in our study, progressively increased over 12 weeks. Our study refutes the findings of immunosuppression by clozapine but finds an immunopotentiating effect. The immunopotentiating effect may be responsible for the side effect profile of clozapine as it has been seen to induce antibodies in the certain patient population, including antineutrophil cytoplasmic antibody-associated vasculitis through a possible IgG-associated mechanism.,
The strength of the study is that it is prospective, in vivo study carried over 12 weeks. Immunoglobulin levels were compared over 12 weeks between the risperidone and clozapine groups along with changes in clinical profile.
The limitation of the study includes that typing of the antibodies toward an antigen was not done. As patients inducted in the study had a longer duration of illness, thus effect of the earlier drugs used on IgG levels cannot be ruled out. Another limitation is the small sample size which hampers the result from being generalized.
Nevertheless, it is a novel study that adds to the literature of neuroimmunology and pharmaco-immunology of schizophrenia.
| Conclusion|| |
It can be concluded from the index study that the response of patients with schizophrenia does not differ much concerning the effect of risperidone and clozapine on the immunoglobulin levels. Yet, clozapine is associated with a significant increase in IgG levels indicating the role of clozapine in the neuroimmunology of schizophrenia.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]