Ketamine has been shown to be a very effective anti-depressant in patients with treatment-resistant depression (TRD) with up to 71% positive response rate in these cohorts [1]. It acts as an N-methyl-D-aspartate (NMDA) receptor antagonist with glutamate blocking capacity and onset of action much faster than conventional antidepressant medications [1,2]. Depending on the mode of delivery, the anti-depressant effects from ketamine administration can be seen within minutes to hours and the benefits can last for days to weeks [1,2].

Common symptoms of ketamine induced cystitis (KIC) include urinary urgency, polyuria, dysuria, incontinence and haematuria, progressing to incontinence, haematuria, ulcerative cystitis, hydronephrosis, bladder wall fibrosis and chronic kidney failure [5,6,9].

Regular ketamine use is associated with increase in LUTS by up to 3-4 times compared to healthy individuals. Urinary symptoms can occur in over 25% of those who use ketamine recreationally and this is directly correlated with dose and frequency of ketamine use [3]. If ketamine cessation occurs early, the urinary symptoms can improve and early damage can reverse [4].

We present a case of a 28-year-old female who was started on ketamine treatment for depression, who developed symptoms of cystitis, which was confirmed by urine microscopy, culture and analysis. To our knowledge, this is the first reported case of ketamine-induced cystitis in a patient receiving treatment-dose ketamine for antidepressant therapy.

Over 350 million people in the world suffer from depression and about one third of these patients are believed to have treatment-resistant depression (TRD) [7]. TRD is often defined as failure to two antidepressant medications [8].

Ketamine has been shown to be a novel and exciting anti-depressant in patients with treatment-resistant depression (TRD), with up to 71% positive response rate [1]. It acts as an N-methyl-D-aspartate (NMDA) receptor antagonist with glutamate-blocking capacity and onset of action much faster than conventional antidepressant medications [1,2]. Depending on the mode of delivery, the anti-depressant effects can be seen within minutes to hours and the benefits can last for days to weeks [1,2].

KIC typically starts with urinary symptoms, including dysuria, urgency, polyuria, nocturia and progressing to incontinence, haematuria, bladder wall fibrosis and ulcerative cystitis. Continuation of the drug can lead to involvement of the upper renal tract, including hydronephrosis and chronic kidney failure [5,6,9]. Physical examination and investigations may show suprapubic pain, sterile pyuria and increased eosinophils within the bladder wall [9].

Imaging of the bladder in severe cases may show a grossly constricted with thickened walls [9]. Cystoscopy often demonstrates a friable bladder mucosa that is prone to bleeding [9]. Microscopically, the urothelium may appear denuded, ulcerated and infiltrated by inflammatory cells, such as mast cells and eosinophils. Other findings include, submucosal fibrosis, muscle hypertrophy and collagen deposition [11].

Although the exact pathogenesis of ketamine induced cystitis is not yet fully understood, various mechanisms have been postulated and it is likely that several pathways are involved concurrently [10].

One theory is that the ketamine and its metabolites, which are largely excreted by the urinary tract, cause direct toxicity to the bladder. These disrupt the urothelial integrity of the bladder epithelium and initiate interstitial fibrosis. This has been demonstrated in animal models and the level of damage directly correlates with the dose of ketamine used [12].

Another theory is an IgE mediated response. Bladder samples in ketamine users frequently show raised inflammatory cells and messengers, including mast cells, eosinophils, COX-2 (cyclo-oxygynase-2), NOS (nitric oxide synthase) and IgE. These levels fall once the patient is in remission from ketamine use and rise again once ketamine use restarts. This suggests an inflammatory response or a hypersensitivity reaction leading to bladder damage [9,12].

Ketamine can also directly stimulate various chemicals, including adenosine triphosphate, antiproliferative factor, and oxidative stress which lead to changes in the bladder wall [9]. It has been reported that the N-methyl-D-aspartate receptor (NMDAR) and angiogenic factors can also cause microvascular injury in the bladder [9].

Other proposed theories include aberrant neurotrophic factors, protein kinase B, mTOR pathways and metadherin and MAPK pathways leading to downstream fibrosis of the bladder [9].

Early diagnosis of ketamine induced cystitis and immediate cessation of ketamine usage has been shown to improve symptoms, reverse early disease and prevent further damage [9].