Serotonergic influence on the levels of prolactin in depressed females
- *Corresponding Author:
- Sangeeta Singhal
Department of Physiology, J. N. Medical College
Aligarh Muslim University, Aligarh 20200, India
Accepted date: February 07 2008
The aim of this study was to evaluate the relationship of serotonin level after treatment with selective serotonin reuptake inhibitors in patients of unipolar depression and influence of serotonin on the secretion of prolactin. Twenty two depressed females of child bearing age, who had come for the first time in the Psychiatry Department were selected for this study. They were subjected to Hamilton rating scale and divided into mild, moderate and severe cases. Their urinary 5-hydroxy tryptamine (5-HT), 5-Hydroxy indole acetic acid (5-HIAA) and serum prolactin levels were estimated before and after 6 weeks of treatment with sero-tonin reuptake inhibitors. The treatment schedule decreased urinary 5-HIAA level signifi-cantly, but there was a non-significant increase in urinary 5-HT. There was also a slight in-crease in serum levels of prolactin. The results suggest that time period required for altera-tion in central neuronal serotonin may be longer than the duration of treatment with sero-tonin reuptake inhibitors.
Unipolar depression, serotonin, prolactin, selective serotonin reuptake inhibitors.
Depression is a common illness, which affects 20% of all women in their life time. The prevalence among women of child bearing age is 10% , among pregnant women is 4-10% while during post partum it is found to be 10-28%. Pregnancy and post partum depression seem to have biological roots within the rapidly shifting hormonal mileu. However, no evidence so far suggests that gonadal hormone, prolactin or thyroid hormone is in any way di-rectly linked to depression. Alteration in the serotonin metabolism seems to be an important factor in the etiol-ogy of depression. It has been shown that depletion of serotonin in certain areas of the brain has a great impact in contributing to depression [2,3,4,5]. It has been pro-posed that enhancement of central serotonergic transmis-sion may underlie the therapeutic response to different types of antidepressant drugs [6,7]. It has moreover been observed that serotonin has a stimulatory effect on the release of prolactin and serotonin depletion plays a role in pathogenesis of depression as drugs like selective sero-tonin reuptake inhibitors (SSRI’s) tend to cause a dra-matic improvement in patients with depression [7,8,9]. However, studies have not been conducted to identify the relationship between the levels of serotonin after treat-ment with SSRI’s in cases of depression and the changes in prolactin level. Present study was, therefore conducted to elucidate the relationship between the levels of sero-tonin before and after SSRI treatment in cases of depres-sion and its association with the secretion of prolactin.
Material and Methods
Twenty two patients with depression were selected from the out patient Department of Psychiatry of J. N. Medical College, Aligarh Muslim University, Aligarh, on their first visit. Prior consent was taken from all the subjects.
The subjects were of child bearing age (18-45 years) and were diagnosed as depressives under the strict guidelines of DSM-IV criteria . Blood samples and a 24-hour urine sample with 25 ml of glacial acetic acid as preserva-tive were collected from these subjects. The serum was separated by centrifuging the blood sample at 3000 rpm for 15 minutes and was stored at –20°C. The urine sam-ples were stored at 4°C. The pretreatment levels of urinary 5-HIAA, 5-HT and serum prolactin were estimated.
The patients were then advised to start the treatment with SSRI’s (Sertraline - 50-200 mg/day). The follow up sam-ples of the blood and urine were again collected after six weeks of treatment of SSRI’s . The levels of 5-HIAA and 5-HT of the patients were then estimated from the urine samples . Serum prolactin level was estimated prior to the start of medication and then after 6 weeks of drug schedule by Enzyme linked immunosorbent assay . Stastical analysis was done by Student’s t-test.
Twenty two depressed females were included in this study with a mean age of 28±4.0 years and median of 28 years. These patients were subjected to Hamilton rating scale for depression. On the basis of these scores, 9 (41%) cases were diagnosed mild, 11 (50%) cases as moderate and 2 (9%) cases as severe depression.The levels of urinary 5-HT, 5-HIAA and serum prolactin were measured before treatment and the values were compared between the mild and moderate cases. The mean 5-HT was 9.0±2.32μmol/L. in mild cases of depres-sion and it was 8.0±1.56 μmol/L. in moderate cases and was not significantly different. The levels of 5HIAA in mild cases of depression were found to be 15.6±6.09 μmol/L .and 15.7±3.66 μmol/L in moderate cases, respe-ctively but was not significantly different. Serum con-centration of prolactin of the mild depressed cases was recorded to be 9.0±6.62 ng/mL and in moderate cases was 8.65±4.59 ng/mL, respectively. The values were not significantly different (Table-I). The levels of 5-HT, 5-HIAA in urine and serum prolactin were estimated after 6 weeks of treatment with SSRI’s in cases of mild and moderate depression (Table I).
A comparison was made between the pretreatment and post treatment values obtained in mild depression and moderate depression groups. However, no significant dif-ference was noted between the pretreatment and post treatment values of the various metabolic hormones (Fig. I).
In another study, patients of different severity were mixed and their pre and post-treatment 5-HT, 5-HIAA and se-rum prolactin levels were compared for significance. There was a significant decrease in concentration of 5-HIAA of the subjects treated with selective serotonin re-uptake inhibitors. Although there was a slight increase in 5-HT level in post- treatment group yet it was not found to be statistically significant. An increase in serum prolac-tin levels was observed after treatment with serotonin re-uptake inhibitors, but it was significant too (Figure I).
After 6 weeks of treatment with selective serotonin reup-take inhibitors, all the patients were again subjected to HAMD scoring for depression. There was some im-provement in the condition of the patients in general. Out of 22 cases, 2 patients had score <7 i.e. normal, 18 pa-tients had scores of mild depression and 2 patients had score of moderate depression i.e. 9% patients became normal, 82% remained mildly depressed and 9% re-mained moderately depressed.
The present study included female patients of depression. They all were of childbearing age (18-45 years). The pa-tients were divided into groups according to the severity of depression, assessed by HAMD scores before starting the treatment . The levels of urinary 5-HT, 5-HIAA and serum prolactin were measured and compared before the start of treatment and after 6 weeks of treatment. The pre- and post-treatment urinary 5-HT, 5HIAA and serum prolactin levels were compared for significance but none of the compared groups showed any significant differ-ence. The patients of different severity score were mixed and again the pre- and post-treatment urinary 5-HT, 5-HIAA and serum prolactin levels were compared for sig-nificance, as shown in Table I. It was, however, observed that there was a slight increase in urinary 5-HT level in post-treated patients as compared to untreated patients, yet it was non-significant (Figure-I). Evidences suggest that serotonin reuptake inhibitors reduce the Vmax of 5-HT uptake in the platelets as depicted by stain et al , therefore, the plasma 5-HT levels are expected to rise. Treatment of depressed patients with SSRI’s caused a marked decrease in platelet 5-HT uptake in studies made by Lawrence et al  and Bakish et al . But in this study the increase in urinary 5-HT levels in post-treated patients is not significantly higher than in untreated pa-tients. An increase in 5-HT of 0.1% only over the pre-treatment group is inexplicable. As evidences regarding the time duration for increase in 5-HT levels either central or peripheral are lacking, it is possible that time period for alteration in central neuronal serotonin levels may be longer than the duration of SSRI treatment of 6 weeks. However, slight improvement in urinary 5-HT levels in-dicate the efficacy of drugs, also evident in the form of decrease in HAMD scores in these patients. Thus, the results of this study is in consonance with the findings of Sheline et al .
Further, a significant decrease in urinary 5-HIAA level was observed in post-treated patients. This could be due to pre-synaptic neuronal inhibition of serotonin uptake by these drugs resulting in an increased synaptic concentra-tion of serotonin, which permits increased activation of receptors and also prevent serotonin from being metabo-lized by MAO which results in decreased level of its me-tabolite, 5-HIAA in urine. This finding is also in conso-nance with the study made by Sheline et al .
A slight increase in the serum prolactin level was also observed in the post-treated groups with SSRI’s as com-pared to the untreated group. However, the increase was not statistically significant. Earlier studies by Meltzer et al  have clearly shown that antidepressants i.e., SSRI’s increases central serotonergic activity in patients by pre-synaptic mechanism which potentiates the secretion, so the findings of our study correspond with the findings made by Meltzer et al .
To conclude, the evidences regarding the time duration for significant change in 5-HT levels are lacking, so it is quite possible that time period required for significant alteration in central neuronal serotonin may be longer than the duration of SSRI treatment of 6 weeks. Morover, improvement in the depressive state of the patient but not the serotonergic status suggests that perhaps the duration of hyposerotonergic state is more important than the magnitude of decrease in serotonin levels.
- Misri S. Margerate Duke. Journal of Society of Obstet-rics and Gynecology of Canada. 1995; 17: 657-653.
- Asberg M, Thoren P, Traskman L, Bertilsson L, Ring-berger V. Serotonin depression. A biochemical sub-group within the affective disorders? Science 1976; 191: 478-480.
- Ohmori T, Arora RC, Meltzer HY. Serotonergic meas-ures in sucide brain; the concentration of 5-HIAA, HVA and tryptophan in frontal cortex of suicide vic-tims. Biol Psychiatry. 1992; 32: 57-71.
- Coppen A, Turner P, Rowsell AR, Padgham C. 5-hydroxytryptamine (5-HT) in the whole blood of pa-tients with depressive illness. Postgrad Med J 1976 52: 156-158.
- Sarrias MJ, Artigas F, Martinez E, Gelpi E, Alvarez E, Udina C, Casas M. Decreased plasma serotonin in melancholic patients. Biol Psychiatry 1987; 22: 1429-1438.
- Fuller RW. Basic advances in serotonin pharmacology. J Clin Psychiatry 1992 53 (suppl 10) : 36-45.
- Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disorder 1998; 52: 215-235.
- Prange AJ Jr, Wilson IC, Lynn CW, Alltop, LB, Stikeleather RA. L-Tryptophan in mania. Contribution of a permissive hypothesis of affective disorders. Arch. Gen. Psychiatry 1974; 30: 56-62.
- Asberg M, Traskman L, Thoren P. 5-HIAA in the cere-brospinal fluid. A biochemical suicide predictor. Arch Gen Psychiatry 1976 38: 1193-1197.
- Hamilton M. A rating scale for depression Neurosur-gery Psychiatry 1996; 23: 56.
- Janet R Mc Murray, Varley’s Practical Clinical Bio-chemistry, 6th edition, Heinmann Medical books Amino acids (Ch-18) 1975; P 368-398.
- A manual of laboratory technique. J.C.M.R. 1983.
- Strain Malmgren R, Khoury AE, Aberg-Wistedt A, Tham A. Serotonergic function in major depression and effect of sertraline and poroxetine treatment. Clinical Psychopharmacology 2001; 16 (2): 93-101.
- Lawrence KM, Katona CL, Abou-Saleh MT, Robertson MM, Nairac BL, Edwards DR, Lock T, Burns RA, Har-rison DA, Morton RW. Platelet 5-HT uptake sites, la-beled with [3H] paroxetine, in controls and depressed patients before and after treatment with fluoxetine or lofepramine. Psychopharmacology 1994; 115: 261-264.
- Bakish D, Cavazzoni P, Chudzik J, Ravindran A, Hrdina PD. Effects of selective serotonin reuptake in-hibitors on platelet serotonin parameters in major de-pressive disorder. Biol Psychiatry 1997; 41: 184-190.
- Sheline Y, Bardgett ME, Csernansky JG. CSF HIAA study after SSRI treatement. Journal of Clinical Psy-chopharmacology. 1997; 17: 11-14.
- Meltzer H, Bastani B, Jayathilake Maes M. Fluoxetine but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan mediated increase in plasma prolac-tin secretion in subjects with major depression. Neuro-psycho-pharmacology 1997; 17: 1-11.