To compare frequency of Hyperprolactinemia with Risperidone and
Olanzapine in patients with psychosis
The study was a Randomized Controlled Trial
(RCT) conducted in Combined Military Hospital (CMH),Lahore over a period of six
months (1st Sep 2015 to 29 Feb 2016)
SUBJECTS AND METHODS
who had psychosis as a symptom/sign in any of psychiatric illnesses according
to ICD-10 diagnostic criteria were included in this Randomized controlled
Trial. Fasting venous blood samples for serum prolactin were collected between
0800 hrs and 1000 hrs at baseline (first visit). The patients were then
randomly assigned to receive risperidone or olanzapine by lottery method. Serum
prolactin levels were then collected at 3 months follow-up visit. All samples
were tested in labortary of Pathology department, CMH Lahore for measurement of
serum prolactin levels and results were verified by a classified pathologist.
Confounding variables were identified and excluded by exclusion criteria.
A total of 35 patients (58.33%)
developed hyperprolactinemia. The olanzapine group showed 13 out of 30 patients
(43.33%) and risperidone group showed 22 out of 30 patients (73.33%) with
raised prolactin levels with p-value of 0.018 indicating that the difference was
Frequency of hyperprolactinemia is high
with risperidone than with olanzapine in first episode psychosis.
Psychosis (delusions and/or hallucinations) is a feature
of many psychiatric disorders. In psychotic disorders such as Schizophrenia, Acute
and transient psychotic episode it is the primary symptom/sign while in mood
disorders such as Depression, Bipolar affective disorder it occurs secondary to
Antipsychotics are the primary drugs
used to treat psychosis. These drugs are divided into two classes (Typical and
Atypical) based on their tendency to bind Dopamine (D2) receptors.
Typical antipsychotics bind with high
affinity while atypical are said to bind with low affinity. Antipsychotics including atypical are well
known to cause Hyperprolactinemia i.e. increased prolactin levels. Drugs having
high affinity for Dopamine D2 receptors (Haloperidol) have more tendency to
cause hyperprolactinemia1. Atypical antipsychotics due to their low
affinity for Dopamine D2 receptors are less commonly associated but not
completely free of hyperprolactinemic effects. Among atypical antipsychotics
risperidone and amisulpride affect prolactin levels more frequently while clozapine,
olanzapine, quetiapine are prolactin-sparing2, 3.
is secreted by anterior pituitary gland in a pulsatile manner. Secretion of
prolactin is regulated by dopamine, a hormone produced by hypothalamus.
Dopamine has inhibitory effect on secretion of prolactin. It acts on D2
receptors present in lactotrophs of anterior pituitary to decrease secretion of
prolactin. Antipsychotic drugs bind to D2 receptors and block this effect
causing increase in prolactin levels4.
in short term causes galactorrhea, amenorrhea in women while raised prolactin
levels for prolonged period of time predisposes to osteoporosis and cardiovascular
disease. These side effects in turn
lead to poor compliance5, 6.
of the effects of antipsychotic medication on prolactin levels showed that the
incidence of hyperprolactinemia was 90% with haloperidol, 80% with pimozide,
62% with risperidone, 31% with olanzapine while clozapine, quetiapine and
ziprasidone were prolactin-sparing7.
study comparing effects of risperidone and olanzapine on plasma prolactin
levels both in short and long term showed that a significantly higher
percentage of patients developed hyperprolactinemia in the risperidone
treatment group (89%) compared with olanzapine treatment group (45%) at 3
rationale of this study is based on the fact that previous studies have yielded
inconsistent results regarding frequency of hyperprolactinemia in patients
treated with antipsychotic medication, risperidone and olanzapine9.
The occurrence of hyperprolactinemia with these two commonly used
antipsychotics (olanzapine and risperidone) needs to be clearly evaluated to
help clinicians choose the appropriate drug according to patient’s needs.
MATERIALS AND METHODS:
60 subjects were enrolled in this RCT. Both
males and females, age ranging between 18-60 years (Mean+SD 36.77+9.686), who had psychosis(delusions/hallucinations) as
symptom/sign in any of the various psychiatric illnesses according to ICD-10
diagnostic criteria and had normal serum prolactin levels (below 20 µg/L in
males and below 25 µg/L in females) at the start of study were included. Criteria
that excluded patients from the study included physiological conditions (eg; pregnancy, lactation), medical
Pituitary tumors, Primary hypothyroidism, Adrenal disorders) and
concurrent medications (e.g.
metoclopramide, methyldopa, verapamil, dopamine agonists)
known to affect serum prolactin levels.
The study was carried out in Combined Military
Hospital (CMH), Lahore over a period of six months (1st Sep 2015 to
29 Feb 2016).
approval was obtained from ethical research committee of the hospital and
formal written informed consent was obtained from all the patients included in
Demographic data was collected
regarding age, gender, occupation, education, marital status. Patients
suffering from various psychiatric illnesses were diagnosed by ICD-10 criteria after
history and mental state examination by resident/consultant psychiatrist. The
patients were randomly assigned to receive risperidone or olanzapine by lottery
method. Fasting venous blood samples for serum prolactin were collected between
0800 hrs and 1000 hrs at baseline (first visit) and then at 3 months follow-up
visit. Samples were sent to pathology department (CMH Lahore) for measurement
of serum prolactin levels and results verified by a classified pathologist.
Confounding variables were identified and excluded by exclusion criteria.
Data was analyzed using SPSS 19.0. Descriptive statistics was
used to calculate qualitative and quantitative variables. Mean and standard deviation was calculated for
quantitative variables (Age). Frequency and percentages were calculated for
qualitative variables (Gender, Hyperprolactinemia). Chi-square test was applied
to compare the frequency of Hyperprolactinemia between the two groups. P-value
of <0.05 was considered as significant. Effect modifiers like age, gender, education, occupation, marital status, type of mental illness were controlled by stratification. For post stratification chi-square test was used. RESULTS Patient baseline characteristics are summarized in Table 1. There were 60 patients, the ages of the patients ranged from the youngest being 19 years to the oldest being 58 years (Mean age +SD 36.77+9.686). 68.3%(n=41) of subjects were males and 31.7%(n=19) of subjects were females. Out of 60 patients 25%(n=15) were single, 66.7%(n=40) were married, 3.3%(n=2) were divorced and 5%(n=3) were widowed. The most common occupation seen was of soldiers [28.3%(n=17)] followed by housewives[16.7%(n=10)]. These 2 categories were followed by unemployed[15%(n=9)] and retired[10%(n=6)]. Most of the patients were matriculate[31.7%(n=19)] followed by uneducated [28.3%(n=17)].Most frequent diagnosis among patients was Depression with psychotic features[28.3%(n=17)] followed by Mania with psychotic features[21.7%(n=13)],Acute and transient psychotic episode[20%(n=12)] Schizophrenia[18.3%(n=11)],and Delusional disorder[11.7%(n=7)] Out of the total 60 patients, 35 patients (58.33%) developed hyperprolactinemia. The frequency of hyperprolactinemia in olanzapine treated group was 13 out of 30 patients (43.33%) and in risperidone treated group it was 22 out of 30 patients (73.33%).Mean dose of olanzapine and risperidone used was 9.58 mg and 4.5 mg respectively. Chi square test was used to compare the frequency of hyperprolactinemia between the two groups. After the application of the test, the p-value was found to be 0.018 (Table 2) which showed that the difference in frequency of hyperprolactinemia was statistically significant between the two groups. The difference in hyperprolactinemia between the two treatment groups was significant in older age group i.e. 41-60 years, females, single patients, housewives and patients having a diagnosis of Acute and transient psychotic episode or Schizophrenia as indicated by their p-values shown in Table 1(P-value< 0.05) showing that there is significant effect of risperidone on development of hyperprolactinemia in these groups of patients. TABLE 1 BASELINE PATIENT CHARACTERISTICS Patient characteristics Hyperprolactinemia Olanzapine Treatment group n=30 Risperidone Treatment group n=30 Total P-value Gender Male Female Present Absent Present Absent 10 12 03 05 12 07 10 01 22 19 13 06 .257 .013 Age 18-40 yrs 41-60 yrs Present Absent Present Absent 11 09 02 08 13 06 09 02 24 15 11 10 0.389 0.005 Marital status Single Married Divorced Widow/widower Present Absent Present Absent Present Absent Present Absent 03 04 10 12 0 01 08 0 12 06 01 01 01 01 11 04 22 18 01 01 01 02 .013 .180 .386 Occupational status Soldiers Housewives Unemployed Retired Present Absent Present Absent Present Absent Present Absent 03 05 01 04 0 02 0 02 05 04 05 0 06 01 02 02 08 09 06 04 06 03 02 04 .457 .010 .023 .221 Educational status Matriculate Uneducated Present Absent Present Absent 04 07 03 06 05 03 06 02 09 10 09 08 .260 .086 TABLE 2 ICD-10 DIAGNOSIS ICD-10 Diagnosis Hyperprolactinemia Olanzapine Treatment group n=30 Risperidone Treatment group n=30 Total P-value Acute and Transient psychotic episode Schizophrenia Delusional Disorder Mania with psychotic features Depression with psychotic features Present Absent Present Absent Present Absent Present Absent Present Absent 02 04 01 02 02 01 05 05 03 05 06 0 08 0 02 02 03 0 03 06 08 04 09 02 04 03 08 05 06 11 .014 .011 .659 .118 .858 Table 3 Comparison of hyperprolactinemia in the two treatment groups Hyperprolactinemia Group assigned to patients Group A Group B (Risperidone) (Olanzapine) Total P-Value Present 13 22 35 0.018 Absent 17 08 25 Total 30 30 60 Chi-square = 5.554 p-value= 0.018 (Significant) DISCUSSION Antipsychotics are psychotropic drugs which are used to treat psychosis. Traditionally they are divided into Typical antipsychotics and Atypical antipsychotics. This classification is based on pharmacological (receptorial) and clinical differences. Typical antipsychotics (eg; Haloperidol) are the drugs which have high affinity for dopamine D2 receptors and have high propensity to cause extrapyramidal side effects and raise prolactin levels. In contrast Atypical antipsychotics (with the exception of risperidone) have less affinity for dopamine D2 receptors and have antagonistic effects at serotonin 5HT receptors. Due to these receptorial differences atypical antipsychotics(olanzapine, quetiapine, clozapine) can cause metabolic syndrome but have less propensity to cause EPS and are relatively prolactin sparing.2,3 Hyperprolactinemia is an important phenomenon associated with antipsychotic medication and affects quality of life and adherence to treatment. In short term it causes galactorrhea, amenorrhea and decreased libido. Prolactin levels if remain elevated for prolonged period of time predisposes to osteoporosis and cardiovascular disease. Previous studies have yielded inconsistent results regarding the prolactin sparing effect of atypical antipsychotics9. The objective of this study was to compare frequency of hyperprolactinemia with Risperidone and Olanzapine in patients with first episode psychosis. This will help clinicians choose the appropriate drug according to patient’s characteristics. In our study we found out that the frequency of hyperprolactinemia in risperidone treated group was greater than olanzapine treated group and the difference reached statistical significance. This finding is in agreement with previous studies which show that risperidone is more likely to cause hyperprolactinemia than olanzapine7,8. The mechanisms that account for this difference are: (1) greater D2 receptor affinity of risperidone as compared to olanzapine10 and (2) a higher pituitary versus striatal D2 receptor occupancy for risperidone as compared to olanzapine11. When patients age was considered the frequency of hyperprolactinemia was greater with risperidone in both age groups A(18-40 yrs) and B (41-60 yrs).However the results reach statistical significance in group B showing that there is significant effect of risperidone on development of hyperprolactinemia in age group 41-60 years. Prolactin regulation is a complex phenomenon with part played by various hormones. Estrogens are known to regulate the prolactin cell mass and its lower levels is responsible for the remarkable decrease in serum prolactin concentration after menopause and possibly explains moderate increase in elderly men due to increased bioavailable estradiol12. Gender wise distribution revealed that the frequency of hyperprolactinemia was greater with risperidone in both males and females. In males the results did not reach statistical significance. In females the results were statistically significant showing that there is significant effect of risperidone on development of hyperprolactinemia in females. This is consistent with previous studies which show that women are more prone to develop hyperprolactinemia with antipsychotics than men13.This finding can be explained by the fact that estrogen regulates prolactin cell mass as already mentioned12. The ICD-10 diagnosis included in our study were Acute and transient psychotic episode, Schizophrenia, Delusional disorder, Mania with psychotic features, Depression with psychotic features. There was significant difference observed in frequency of hyperprolactinemia between risperidone and olanzapine(greater with risperidone than olanzapine) when the diagnosis was Acute and transient psychotic episode or Schizophrenia showing that there is significant effect of risperidone on development of hyperprolactinemia in patients with non-affective psychosis of the above types. This significant effect can be explained by the fact that drug-induced hyperprolactinemia is often a dose-related side effect14.These two disorders are primary disorders of psychosis and higher doses of antipsychotics are needed for remission of psychosis. Marital status of patients revealed increased frequency of hyperprolactinemia in risperidone group and the results reached statistical significance in patients who were single (unmarried) showing that there is significant effect of risperidone on development of hyperprolactinemia in this patient group. In our study 12 out of 15 single patients (80%) had non-affective psychosis (acute and transient psychotic episode, schizophrenia, delusional disorder) and as noted above higher doses of antipsychotics are required to treat non-affective psychosis than psychosis associated with mood disorders. Considering the occupational status of patients, the difference in frequency of hyperprolactinemia reached statistical significance for unemployed. This effect can also be explained by the fact that frequency of unemployment is high in primary psychotic disorders than secondary psychotic disorders and higher doses are required for remission of psychosis as described earlier. In summary, this study suggests that olanzapine and risperidone differ in terms of occurrence of hyperprolactinemia and the difference reach statistical significance. Female gender and a diagnosis of primary psychotic disorders (Acute and transient psychotic disorder, Schizophrenia) are risk factors for development of hyperprolactinemia with risperidone. CONCLUSION We concluded that the frequency of hyperprolactinemia is high with risperidone than with olanzapine. Moreover women and patients with a diagnosis of Acute and transient psychotic episode or Schizophrenia are more prone to develop hyperprolactinemia with risperidone than with olanzapine. REEFERENCES 1. Bilal SM, Rana HM. Effect of typical and atypical antipsychotics on plasma prolactin levels in schizophrenia. J Med Sci 2014; 12:142-6 2. Akkaya C, Kaya B, Kotan Z, Sarandol A, Ersoy C, Kirli S. Hyperprolactinemia and possibly related development of prolactinoma during amisulpride treatment; three cases. J Psychopharmacol 2009; 23: 723-6 3. Jerrell JM, Bacon J, Burgis JT, Menon S. Hyperprolactinemia-related adverse events associated with antipsychotic treatment in children and adolescents. J Adolesc Health 2009;45: 70–6 4. Rosenbloom AL. Hyperprolactinemia with antipsychotic drugs in children and adolescents. Int J Pediatr Endocrinol 2010;2010:159402 5. Muench J, HamerAM. Adverse effects of antipsychotic medications. Am Fam Physician 2010;81: 617–22 6. Wu H, Deng L, Zhao L, Zhao J, Li L, Chen J. Osteoporosis Associated with Antipsychotic Treatment in Schizophrenia. Int J Endocrinol 2013; 2013:167138 7. Roke Y, van Harten PN, Boot AM, Buitelaar JK. Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects. J Child Adolesc Psychopharmacol 2009;19:403–14. 8. Pérez-Iglesias R, Mata I, Martínez-García O, Garcia-Unzueta MT, Amado JA, Valdizán EM, et al. Long-term effect of haloperidol, olanzapine, and risperidone on plasma prolactin levels in patients with first-episode psychosis. J Clin Psychopharmacol 2012;32:804–8 9. 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 10. Nordstrom AL, Farde L. Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients. J ClinPsychopharmacol. 1998;18:305Y310 11. Kapur S, Langlois X, Vinken P, et al. 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;302:1129Y1134 12. Vermeulen A, Kaufman JM, Goemaere S, van Pelt I (2002) Estradiol in elderly men. Aging Male 5: 98–102 13. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003;28(Suppl 2):55–68 14. Smith S, Wheeler MJ, Murray R et al.The effect of antipsychotic–induced hyperprolactinemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002; 22:109–14