INTRODUCTION

Prostatism is a medical condition with clinical and social repercussions diminishing the quality of life. While its most common cause is prostate hyperplasia, it is a condition occurring in relation to any obstruction of the urethra or an increased pressure in the urinary tract. First symptoms are poor urinary flow and straining to void, problems in urine projection, hesitancy before starting to urinate, post-micturition dribble, and the feeling of incomplete bladder emptying (1,2). While less severe cases may be tolerated, in severe states microscopic or macroscopic hematuria can be found in the urine (3). As well as being disease-related, this uncomfortable situation may also be seen as a side effect of the use of opiates or drugs such as α -adrenergic agonists (4).

Venlafaxine is a strong serotonin and noradrenaline receptor antagonist and a weak dopamine receptor antagonist, frequently used in clinical practice as an antidepressant in the treatment of a number of mental conditions such as major depressive disorder or anxiety disorder (5). The strongest dose-related effect is serotonergic, then noradrenergic, and in high doses, the drug also has a dopaminergic effect. Being an effective and well tolerated antidepressant, venlafaxine has a comparatively low profile of side effects, which, as well as its effectiveness, depends on the dose (6). Most commonly seen adverse effects are nausea, vomiting, reduced appetite, diarrhea, dryness of the mouth, constipation, drowsiness, and changes in the liver enzymes (7). Side effects in the urinary system are much rarer. There are case reports in the literature regarding urinary incontinence caused by venlafaxine (8,9). While our literature review identified one case with prostatism (10), we found no reports regarding hematuria.

This case report presents a 55-year-old male patient with prostatism symptoms after venlafaxine use developing hematuria.

CASE

A 55-year-old married male, employed as a worker, presented to our psychiatry clinic complaining of anhedonia, lack of appetite, unhappiness, acedia, and lack of energy. After a detailed anamnesis and mental examination applying DSM-5 criteria, the patient, who did not have a previous psychiatric history, was diagnosed with major depressive disorder. He was started on venlafaxine 75mg/day, which was titrated over 2 weeks up to 150mg/day. The patient scored 46 on the Hamilton Depression Scale and 29 on the Hamilton Anxiety Scale. Three weeks after starting the venlafaxine dose of 150mg/day, the patient came in for a control examination; because of blood found in the urine, frequent micturition, and need to strain while urinating, a urological consultation was requested. The etiological workup for the patient, who did not have any disease and was not on any medication, included blood (full blood, urea, creatinine, prostate-specific antigen, sedimentation, CRP) and urine examination (full urine), urological examination (assessed by detailed anamnesis, examination, laboratory diagnostics, and uroflowmetry), and imaging examinations (ultrasonography, tomography); no results explaining the symptoms were obtained. Consultations in internal medicine and nephrology showed the patient’s renal functions to be normal. Given the temporal correlation between onset of symptoms and starting of venlafaxine use, it was decided to stop the administration of venlafaxine. The patient was started on sertraline 50mg/day. His complaints gradually decreased over the course of two weeks and then disappeared. Upon follow-up, the urological complaints did not recur. Using the Naranjo Adverse Drug Reaction Probability Scale, it was found that venlafaxine-related prostatism and hematuria are “likely drug-related side effects” (Naranjo adverse drug reaction score=6) (11).

DISCUSSION

Psychiatric disorders are frequently seen. In clinical practice, serotonin-noradrenaline reuptake inhibitors (SNRIs) are often chosen for the treatment of these diseases as they have a low profile of adverse drug reactions. To our knowledge, there are no cases in the literature reporting hematuria related with venlafaxine use. However, prostatism has been reported in relation with the use of venlafaxine (10) and milnacipran (12). There are also reports about duloxetine (13) and reboxetine (14) causing similar symptoms. All of these drugs are characterized by noradrenaline reuptake inhibiting properties. In our case, after the use of venlafaxine hematuria and prostatism symptoms started. To our knowledge, our case is the first of its kind to be reported.

It is known that serotonin and noradrenaline play an important role in the organization of the lower urinary system (15). The pudendal somatic motor nucleus of the spinal cord is densely innervated with serotonin (5HT) and noradrenaline terminals. In the light of this information, given that prostatism is seen with agents acting on noradrenaline, such as venlafaxine and milnacipran, but not with serotonin reuptake inhibitors, we may assume that the probable mechanism of this adverse effect could also cause an increase in the extracellular concentration of noradrenaline due to the activation mechanism of venlafaxine in subtypes of the adrenergic receptors (16). Based on this hypothesis, in our case we chose an antidepressant from the SSRI group after the development of adverse effects with venlafaxine.

Normally, a very small number of erythrocytes can be found in the urine unrelated to any particular reason (17). If the erythrocyte number is greater than expected, we can talk about hematuria. Macroscopic (red or brown urine, visible to the naked eye) or microscopic hematuria can occur related to very different causes, either as an isolated symptom or as one of a range of symptoms. While our patient presented with a complaint of hematuria, tolerable prostatism symptoms were also present.

Related to the degree of their serotonin uptake inhibition, antidepressants might affect the serotonin uptake mechanism in the platelets and thus interfere with hemostasis (18). Studies supporting this hypothesis suggest that antidepressants reduce intraplatelet serotonin contents, affect platelet aggregation, and prolong closing time (19). From this perspective, we can assume that the hematuria seen in our case stemmed from the serotonin reuptake inhibition effect of venlafaxine. However, we should not forget the possibility that the hematuria might have been a secondary hemorrhage caused by the physical effects of the symptoms of prostatism.

Side effects of drugs can be assessed with the adverse drug reaction probability scale developed by Naranjo et al. (11) The score ranges between 0 and 13 points, whereby 9 points and above means the effect is “definite,” between 5 and 8 points “probable,” between 1 and 4 points “possible,” and at 0 points “doubtful.” In the assessment according to this scale, our case scored a total of 6 points: 1 point for previous publication reporting hematuria and prostatism related to venlafaxine use, 2 points for onset of hematuria and prostatism after administration of the suspected drug, 1 point for disappearance of side effects after discontinuing the drug, and 2 points for the absence of other detectable possible reasons for hematuria and prostatism. This data suggests that the adverse effect is probably related to venlafaxine.

There are some limitations in this report. In our patient, venlafaxine plasma level determination and cysto-ureteroscopic studies were not done. In addition, these examinations would not have been practical, given that the patient’s complaints resolved after the change of antidepressant.

In conclusion, the presence of hematuria and prostatism symptoms seriously affects the quality of life and social relations. Venlafaxine-related prostatism symptoms are relatively rare and are often tolerable for the patient. However, as no risk factors for venlafaxine-induced hematuria and prostatism are known, clinicians should be careful when prescribing antidepressants acting through noradrenaline mechanisms, particularly venlafaxine. The number of studies reporting effects of venlafaxine use on the urogenital system is limited. In order to illuminate the mechanism of hematuria and prostatism symptoms related to the use of venlafaxine, controlled studies with larger samples are required.

REFERENCES

1. Abrams P. New words for old: lower urinary tract symptoms for “prostatism”. BMJ 1994; 308:929-930. [CrossRef]

2. McConnell JD. The pathophysiology of benign prostatic hyperplasia. J Androl 1991; 12:356-363.

3. Atan A, Tuncel A. Treatment options in benign prostate hyperplasia associated with lower urinary tract symptoms. Turk J Urol 2012; 38:228-232. [CrossRef]

4. Cardozo L. Voiding difficulties and retention. Urogynecology. 1st ed. New York, NY: Churchill Livingstone; 1997: 305-320.

5. Holliday SM, Benfield P. Venlafaxine a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49:280-294. [CrossRef]

6. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356:2059-2063. [CrossRef]

7. Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, Mager U, Gaynes BN, Thieda P, Strobelberger M. Second-generation antidepressants in the pharmacologic treatment of adult depression: an update of the 2007 comparative effectiveness review [Internet] 2011.

8. Polimeni G, Salvo F, Cutroneo P, Nati G, Russo A, Giustini ES, Spina E. Venlafaxine-induced urinary incontinence resolved after switching to sertraline. Clin Neuropharmacol 2005; 28:247-248. [CrossRef]

9. Erdinc A, Gurates B, Celik H, Polat A, Kumru S, Simsek M. The efficacy of venlafaxine in the treatment of women with stress urinary incontinence. Arch Gynecol Obstet 2009; 279:343-348. [CrossRef]

10. Gundogmus I, Ispir M, Bakkal O, Karagoz A, Maden O, Algul A, Ebrinc S. Venlafaxine-induced prostatism: a case report. Psychiatry and Clinical Psychopharmacology 2017; 27:197-198. [CrossRef]

11. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239-245. [CrossRef]

12. Akpinar A. Acute prostatism associated with milnacipran therapy: a case report. Turk Psikiyatri Derg 2009; 20:403-405.

13. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther 1995; 274:1014-1024.

14. Holm KJ, Spencer CM. Reboxetine. A review of its use in depression. CNS drugs 1999; 12:65-83. [CrossRef]

15. Katofiasc MA, Nissen J, Audia JE, Thor KB. Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats. Life Sci 2002; 71:1227-1236. [CrossRef]

16. Jost W, Marsalek P. Duloxetine: mechanism of action at the lower urinary tract and Onuf’s nucleus. Clin Auton Res 2004; 14:220-227. [CrossRef]

17. Abuelo JG. The diagnosis of hematuria. Arch Intern Med 1983; 143:967-970. [CrossRef]

18. Narayan M, Anderson G, Cellar J, Mallison RT, Price LH, Nelson JC. Serotonin transporter-blocking properties of nefazodone assessed by measurement of platelet serotonin. J Clin Psychopharmacol 1998; 18:67-71. [CrossRef]

19. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000; 68:435-442. [CrossRef]