|Ahead of print publication
Can clinical parameters of patients, sans serum prolactin measurement, identify amenorrhea associated with risperidone use? Results from a cross-sectional analytical study
Vigneshvar Chandrasekaran1, Avin Muthuramalingam2, Karthick Subramanian1
1 Department of Psychiatry, Mahatma Gandhi Medical College and Research Institute, Puducherry, India
2 Department of Psychiatry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
|Date of Submission||01-Apr-2022|
|Date of Decision||08-Jun-2022|
|Date of Acceptance||09-Jun-2022|
|Date of Web Publication||17-Sep-2022|
Plot No. 45 and 46, 2nd Cross, Gnanapragasam Nagar, Puducherry - 605 008
Source of Support: None, Conflict of Interest: None
Background: Risperidone is a second-generation antipsychotic, which exerts its action by antagonizing dopamine (D2) and serotonin (5-HT2A) receptors. Amenorrhea is a common adverse effect observed in risperidone. Risperidone blocks the dopamine receptor of lactotroph cells of the pituitary gland, resulting in loss of the inhibitory effect of dopamine on prolactin. The resultant hyperprolactinemia decreases estrogen through its impact on the pulsatile secretion of gonadotropins and ovarian follicular growth leading to amenorrhea. Identifying the associated clinical parameters will aid in predicting the occurrence of amenorrhea in patients on treatment with risperidone, especially in a setting devoid of prolactin estimation. The objective of this study was to compare the clinical profile of patients with and without risperidone-induced amenorrhea.
Methodology: A cross-sectional comparative study was done in a tertiary care hospital. A total of 30 female patients on risperidone who developed amenorrhea were recruited, and age-matched patients on risperidone without amenorrhea were taken as controls. The clinical parameters of the groups were compared using the Mann–Whitney U-test. Binary logistic regression was used to predict the clinical predictors associated with risperidone-induced amenorrhea.
Results: The amenorrhea group had a significantly longer duration of untreated psychosis (DUP) (P = 0.011), duration of total treatment (P = 0.003), and duration of treatment exclusively with risperidone (P = 0.002). No significant differences were noted in the dose of risperidone (P = 0.570) and the diagnosis (P = 0.455) between the groups. However, the regression test did not confer any risk due to any clinical parameters.
Conclusion: Individuals who developed amenorrhea had a longer DUP and a longer duration of treatment exclusively with risperidone.
Keywords: Clinical parameters, duration of untreated psychosis, risperidone, risperidone-induced amenorrhea
|How to cite this URL:|
Chandrasekaran V, Muthuramalingam A, Subramanian K. Can clinical parameters of patients, sans serum prolactin measurement, identify amenorrhea associated with risperidone use? Results from a cross-sectional analytical study. J Curr Res Sci Med [Epub ahead of print] [cited 2022 Oct 4]. Available from: https://www.jcrsmed.org/preprintarticle.asp?id=356210
| Introduction|| |
The use of antipsychotics is marred by the potential metabolic, motor, and cardiac adverse effects. In addition, the first-generation and certain second-generation antipsychotics (SGAs), such as risperidone and amisulpride, are known to cause hormonal adverse effects, especially increased prolactin levels. Hyperprolactinemia can result in changes in the menstrual cycle, such as amenorrhea and oligomenorrhea, galactorrhea, and decreased libido.
Antipsychotic-induced amenorrhea occurs due to dopamine receptor blockade in the lactotroph cells of the pituitary gland. The blockade results in the loss of the inhibitory effect of dopamine on prolactin secretion, leading to hyperprolactinemia. Hyperprolactinemia, in turn, induces amenorrhea by decreasing estrogen levels through its effects on the pulsatile secretion of gonadotrophins and follicular growth in the ovary. The propensity to develop antipsychotic-induced amenorrhea is contingent on the dosage, length of exposure to the antipsychotic, concomitant medications, and the presence of endocrinological or gynecological morbidity.,
Apart from antipsychotics, psychosocial stressors inhibit the hypothalamic–pituitary–ovarian axis leading to amenorrhea through hypoestrogenism and hyperprolactinemia., Further, schizophrenia patients have been found to have alterations in the hypothalamic-pituitary axis (HPA), leading to estrogen deficiency which results in euprolactinemic amenorrhea.
Risperidone is a SGA which is a dopamine (D2) and serotonin (5-HT2A) receptor antagonist. Risperidone crosses the blood–brain barrier poorly and hence has a longer duration of dopamine receptor blockade in the pituitary gland compared to other SGAs, increasing its propensity to cause amenorrhea. Review studies have shown that the prevalence of risperidone-induced hyperprolactinemia varies from 72% to 100%. A comparative study among women on antipsychotics showed the prevalence of hyperprolactinemia to be 88% in risperidone users in contrast to 47% in patients on first-generation antipsychotics. The prevalence of amenorrhea in patients taking risperidone varied between 10% and 48% in previous studies. Studies from India showed a prevalence of risperidone-induced amenorrhea to be between 45% and 70%.,
Risperidone-induced amenorrhea is a source of distress and stigma in patients leading to poor compliance with treatment. Long-term physical effects of increased prolactin levels include a decrease in bone mineral density, early menopause, an increase in breast and uterine carcinoma, and cognitive deficits. The above findings, along with resultant infertility in the reproductive age group women, warrant early detection and management. Furthermore, knowing possible clinical parameters that confer a high risk of hyperprolactinemia in patients on risperidone helps in early detection, especially in situations where there are constraints on affordability and availability of prolactin measurement. Hence, we aim to compare the clinical profile of patients who developed amenorrhea after risperidone intake with those who did not develop amenorrhea in a setting devoid of serum prolactin estimation.
| Materials and Methods|| |
Study design and setting
The study was a cross-sectional study carried out in the department of psychiatry of a tertiary care hospital in the southern part of India for 1 year.
Eligibility criteria and sample size
Female participants between 18 and 45 years of age who had been diagnosed with any Axis-I psychiatric disorder according to the International classification of disease-10, Diagnostic criteria for research, and on treatment with risperidone were recruited. Secondary amenorrhea due to risperidone was considered when there was an absence of menstruation in three consecutive cycles in patients who had regular cycles previously and when the onset of amenorrhea was after initiation of risperidone.
After getting informed consent, a total of 30 participants who developed amenorrhea after risperidone intake were recruited. An equal number of consenting age-matched participants on risperidone without amenorrhea were taken as controls. Individuals on other concomitant psychotropics were excluded from the study. Participants with a history of abnormal menstrual cycles or gynecological disorders were excluded from the study. Participants with medical disorders encompassing endocrinological, metabolic, and neurological disorders and those on medications affecting the menstrual cycle were excluded from the study. The information about concomitant drug intake and medical and gynecological disorders was collected through history taking and file review. All the recruited patients who developed amenorrhea were managed appropriately.
A semi-structured pro forma was utilized to collect sociodemographic, clinical, and treatment parameters of the participants, such as age, diagnosis, duration of untreated psychosis (DUP), duration of total treatment and treatment with risperidone, and dose of risperidone. Informed consent was taken from the patient and the legally accepted representative. The institutional ethics committee clearance was obtained before the commencement of the study (IEC/C-P/41/2019).
The normality of the data was assessed using the Kolmogorov–Smirnov test. Continuous variables were expressed as median with interquartile range (IQR), and the Mann–Whitney U-test was used to compare the two groups as they were nonnormal in distribution. Discrete variables were expressed as frequencies and percentages and were compared using the Chi-square test. The adjusted odds ratio of the clinical predictors of risperidone-induced amenorrhea was calculated using binary logistic regression. All statistical analyses were done at 95% confidence interval, and a P < 0.05 was considered statistically significant. Data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 18.0 (SPSS Inc., Chicago, IL, USA).
| Results|| |
A total of 30 cases and an equal number of age-matched controls were recruited. The mean (± standard deviation) age of cases was 31.97 (±6.98) years, and that of controls was 32.03 (±7.41) years. There was no significant difference in age between the two groups (U = 444.500; P = 0.935) [Table 1].
Based on the diagnosis, psychosis not otherwise specified was the major diagnosis comprising 43% in cases and 33% in controls, followed by acute and transient psychotic disorder and others [Table 2]. All patients, in addition to risperidone, were on benzodiazepines and trihexyphenidyl. Patients who developed amenorrhea with risperidone were either cross tapered or augmented with aripiprazole.
The median (IQR) DUP in cases was 8 (4.00–12.00) months and was significantly higher compared to controls whose duration was 4 (3.00–6.50) months (U = 280.00, P = 0.011). Similarly, there was a significant difference in the total duration of treatment of illness and duration of treatment exclusively with risperidone between cases and controls. The median (IQR) total duration of treatment was 10.5 (6.00–12.75) months for cases while it was 6 (4.75–8.00) months for controls (U = 250.500, P = 0.003). The median (IQR) duration of treatment exclusively with risperidone was 9 (6.00–12.00) months compared to 6 (4.00–8.00) in controls and was found to be significantly different (U = 242.500, P = 0.002). However, there was no significant difference in dosage between the two groups (U = 414.500, P = 0.570). Binary logistic regression showed that DUP, total duration of treatment of illness, and duration of treatment exclusively with risperidone did not confer any additional risk [Table 3].
| Discussion|| |
The study compared the clinical characteristics between the groups of those individuals on risperidone with and without amenorrhea. Age-related variation of prolactin levels recorded in the literature has been addressed by age matching of controls in the current study.
DUP is the time elapsed between the onset of psychotic symptoms and the time of initiating treatment. In the current study, DUP was significantly longer in cases compared to controls which can be explained by the synergistic effect of neurotoxicity of the disease and the purported effect of risperidone on the HPA., The above finding is supported by a comparative study revealing the presence of a longer DUP and a severe symptom profile in a hyperprolactinemic group of schizophrenic patients.
The amenorrhea group in the current study was found to have an increased total duration of treatment which can be explained by the effect of long-term antipsychotic use in such patients. The above finding is in line with a previous study revealing that a longer duration of treatment with antipsychotics is associated with menstrual irregularities and hyperprolactinemia.
Participants who developed amenorrhea were on treatment with risperidone for a significantly longer time compared to the controls. Prolactin-stimulating antipsychotics are associated with drug-induced amenorrhea. Risperidone is considered a prolactin-stimulating antipsychotic and hence the longer duration of treatment with risperidone can be considered a risk factor for menstrual changes.
There was no difference in the dosage of risperidone between groups, similar to a previous study reporting no correlation between the dosage and amenorrhea. The above finding has to be taken with caution considering the relatively smaller sample size in the current study and with earlier studies with larger samples reporting antipsychotic-induced amenorrhea to be dose-dependent.,
The strengths of the study being one of the few pragmatic psychopharmacological studies assessing clinical parameters of risperidone-induced amenorrhea in India and the presence of an age-matched control group which could have negated the age-related variations in menstruation. Serum prolactin estimation is frequently unavailable in resource-limited settings and has a bearing on the economic burden of the patient and the caregivers, and hence the evaluation of amenorrhea by clinical parameters could be vital in such settings.
The study had the following limitations. Comparatively larger sample size and adding a few more clinical parameters, such as the severity of psychiatric symptoms and amenorrhea would have ascertained our conclusions better. The use of a medication adherence scale could have provided a more reliable measure of adherence to antipsychotics which could have an effect on the development of amenorrhea. The evaluation of psychosocial stressors and lifestyle factors could have provided more insights into the interplay of factors leading to amenorrhea in patients with psychiatric illness.
| Conclusions|| |
The study showed that the duration of untreated psychosis, total duration of treatment of illness, and duration of treatment exclusively with risperidone were significantly higher in the group which developed amenorrhea, however, none of them conferred any additional risk. The current study would help clinicians in understanding the relationship between the clinical profile of the patient and the propensity to develop risperidone-induced amenorrhea. The above findings will be highly relevant in a resource-limited setting which is devoid of serum prolactin estimations. The study emphasizes clinicians to have a high degree of suspicion of amenorrhea in patients on risperidone who had a longer DUP and longer duration of treatment with risperidone. The presence of longer DUP in individuals with antipsychotic-induced amenorrhea implicates the need for further research into the neurotoxicity hypothesis of the illness and its correlates through imaging and receptor binding studies. Although there were significant differences in the clinical parameters between the two groups, none could confer risk for risperidone-induced amenorrhea. Studies with a larger sample size are required in the future to support or refute the current study's observations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics – A review. Hum Psychopharmacol 2010;25:281-97.
Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: Mechanisms, clinical features and management. Drugs 2004;64:2291-314.
Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: A pharmacological analysis in rats. J Pharmacol Exp Ther 2002;302:1129-34.
Grattan DR, Jasoni CL, Liu X, Anderson GM, Herbison AE. Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology 2007;148:4344-51.
Yasui-Furukori N, Saito M, Nakagami T, Sugawara N, Sato Y, Tsuchimine S, et al
. Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:537-40.
Montgomery J, Winterbottom E, Jessani M, Kohegyi E, Fulmer J, Seamonds B, et al
. Prevalence of hyperprolactinemia in schizophrenia: Association with typical and atypical antipsychotic treatment. J Clin Psychiatry 2004;65:1491-8.
Aston J, Rechsteiner E, Bull N, Borgwardt S, Gschwandtner U, Riecher-Rössler A. Hyperprolactinaemia in early psychosis-not only due to antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1342-4.
Genazzani AD. Neuroendocrine aspects of amenorrhea related to stress. Pediatr Endocrinol Rev 2005;2:661-8.
, Goff DC, Amico E. Relationship of gender and menstrual status to symptoms and medication side effects in patients with schizophrenia. Psychiatry Res 1998;77:159-66.
David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;22:1085-96.
Bargiota SI, Bonotis KS, Messinis IE, Angelopoulos NV. The Effects of Antipsychotics on prolactin levels and women's menstruation. Schizophr Res Treatment 2013;2013:502697.
Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Hyperprolactinemia in response to antipsychotic drugs: Characterization across comparative clinical trials. Psychoneuroendocrinology 2003;28 Suppl 2:69-82.
Savarimuthu MK, Bhaskar S, Alexander AM, Kurian S. A cross sectional study on antipsychotic induced amenorrhoea in women attending a tertiary care centre in South India. Int J Res Med Sci 2019;7:2067-71.
Kelly DL, Powell MM, Wehring HJ, Sayer MA, Kearns AM, Hackman AL, et al.
Adjunct aripiprazole reduces prolactin and prolactin-related adverse effects in premenopausal women with psychosis: Results from the daamsel clinical trial. J Clin Psychopharmacol 2018;38:317-26.
Montejo ÁL, Arango C, Bernardo M, Carrasco JL, Crespo-Facorro B, Cruz JJ, et al
. Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia. Rev Psiquiatr Salud Ment 2016;9:158-73.
DA, Poth MA. Amenorrhea: An approach to diagnosis and management. Am Fam Physician 2013;87:781-8.
Norman RM, Malla AK. Duration of untreated psychosis: A critical examination of the concept and its importance. Psychol Med 2001;31:381-400.
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52:998-1007.
El Sayed El Taweel M, Abdalla AM. Evaluation of prolactin levels in male patients with first-episode schizophrenia and its correlation with psychopathology: Middle East Curr Psychiatry 2017;24:49-54.
Alosaimi FD, Fallata EO, Abalhassan M, Alhabbad A, Alzain N, Alhaddad B, et al
. Prevalence and risk factors of hyperprolactinemia among patients with various psychiatric diagnoses and medications. Int J Psychiatry Clin Pract 2018;22:274-81.
Milano W, D'Acunto CW, De Rosa M, Festa M, Milano L, Petrella C, et al
. Recent clinical aspects of hyperprolactinemia induced by antipsychotics. Rev Recent Clin Trials 2011;6:52-63.
Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
Suzuki Y, Sugai T, Fukui N, Watanabe J, Ono S, Tsuneyama N, et al
. Differences in plasma prolactin levels in patients with schizophrenia treated on monotherapy with five second-generation antipsychotics. Schizophr Res 2013;145:116-9.
[Table 1], [Table 2], [Table 3]