Urinary Retention Triggered by Urethritis in Olanzapine-induced Diabetic Ketoacidosis

Abstract

A 58-year-old woman with schizophrenia was transported to our hospital by ambulance due to impaired consciousness. At the time of the examination, the patient had significant abdominal distension and diabetic ketoacidosis associated with urinary retention. Although the symptoms improved with the insertion of a urinary catheter and glycemic control, the involvement of the antipsychotic olanzapine was considered the background to the pathophysiology of this case. We herein report the relationship between antipsychotic drugs, diabetic ketoacidosis, and urinary retention along with a literature review.

Introduction

Olanzapine is an atypical antipsychotic with a chenobenzodiazepine backbone that is relatively well tolerated in schizophrenia with fewer side effects (e.g. extrapyramidal symptoms) than conventional antipsychotics, resulting in its increasingly frequent prescription (1). However, as its use in patients with schizophrenia has become more widespread, there have been increasing reports of its adverse effects on blood glucose levels, such as the onset of diabetes or worsening of glycemic control associated with olanzapine (2-5).

Glucose intolerance caused by olanzapine often leads to diabetic ketoacidosis (6-9). Epidemiological data have shown that patients receiving olanzapine have an approximately 10-fold higher risk of developing diabetic ketoacidosis than the general population (10). The detailed mechanism of olanzapine-induced diabetes is not known, but weight gain is reportedly associated with increased appetite followed by insulin resistance (11-17), although atypical diabetes development without obesity has also been reported (18-20).

We herein report a patient with schizophrenia who experienced diabetic ketoacidosis and marked urinary retention while receiving olanzapine.

Case Report

A 58-year-old woman had been diagnosed with schizophrenia at 34 years old and had received regular outpatient treatment at a psychiatric hospital. She was taking the antipsychotic levomepromazine and olanzapine as well as the sleeping pill nitrazepam. About five years ago, she had become aware of dry mouth but never been scrutinized. Five days before hospitalization, she suddenly experienced difficulty walking, repeatedly fell, and was sometimes unable to urinate in the toilet. She was unable to move on the day of hospitalization because of numbness in both lower limbs; therefore, her family requested an emergency visit, and she was brought to our hospital.

At the time of the visit, her consciousness was clear, and there was no paralysis of the lower limbs. However, her Achilles tendon reflex and sense of vibration were reduced in both lower limbs. Multiple bruises were found on both lower legs. The blood pressure was 139/86 mmHg, heart rate, 110 beats/min; body temperature, 35.9℃; respiratory rate, 28 breaths/min; and oxygen saturation, 98%. Although there were no abnormalities in heart sounds or auscultation findings in the pulmonary field, there were significant differences in the abdomen. Computed tomography showed significant bladder dilation (lateral diameter, 16.9 cm; anterior and posterior diameter, 15.0 cm; longitudinal diameter, 19.3 cm) and renal pelvis enlargement (Fig. 1). The urethral orifice was severely displaced when the urinary catheter was inserted, and approximately 3 L of urine was excreted after catheterization. A blood examination revealed an impaired renal function, significantly elevated C-reactive protein (CRP) levels, marked hyperglycemia (919 mg/dL), and high HbA1c (17.6%) levels; furthermore, her urine was positive for ketones (3+). An arterial blood gas analysis revealed a pH of 7.120, PaCO₂ of 25 mmHg, PaO₂ of 110.3 mmHg, and HCO₃^- of 10.3 mmol/L, indicating hyperglycemic ketoacidosis (Table). Based on these results, hospitalization was deemed necessary.

Figure 1.

Computed tomography. a: Axial view, b: Coronal view.

Table.

Laboratory Investigation.

Hematology			Blood chemistry						Arterial blood gas analysis (room air)
WBC	13,950	/μL	TP	7.1	g/dL	Na	125	mEq/L	pH	7.120
RBC	421×104	/μL	Alb	3.2	g/dL	K	4.2	mEq/L	PaCO2	25.0	mmHg
Hb	11.2	g/dL	T-Bil	0.44	mg/dL	Cl	88	mEq/L	PaO2	110.3	mmHg
Hct	35.1	%	AST	25	U/L	PG	919	mg/dL	HCO3-	10.3	mmol/L
Plt	40.4×104	/μL	ALT	20	U/L	HbA1c	17.6	%
			LDH	384	IU/L	Serum C-peptide	13.7	μg/day
Urinalysis			CK	239	IU/L	Anti-GAD antibody	<5.0	U/mL
Glucose	(4+)		Amylase	27	U/L	Insulin auto-antibody	<0.4	U/mL
Protein	(1+)		BUN	44.9	mg/dL
Occult blood	(-)		Cr	2.53	mg/dL
Ketone	(3+)		CRP	20.33	mg/dL
			TSH	2.75	μIU/mL

Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CRP: C-reactive protein, Cr: creatinine, CK: creatine kinase, Hb: hemoglobin Hct: hematocrit, LDH: lactate dehydrogenase, PG: plasma glucose, Plt: platelet, RBC: red blood cells, T-Bil: total-bilirubin, TP: total protein, TSH: thyroid-stimulating hormone, WBC: white blood cells

After hospitalization, continuous insulin administration was initiated, along with fluid replacement. Antibiotics (tazobactam/piperacillin 9.0 g/day) were administered due to the possibility of urethritis as an infection. Abdominal distention disappeared after urinary catheterization. Continuous insulin administration lowered the blood glucose to 200-300 mg/dL. The patient started eating on the third day of hospitalization, and the insulin was changed to subcutaneous administration using a scale. Metformin was administered orally. However, the blood glucose levels were insufficiently improved in the 200-300 mg/dL range. On day 9 of hospitalization, a blood examination confirmed that the inflammatory changes and renal dysfunction had resolved, and oral olanzapine was discontinued. After discontinuation of olanzapine, the blood glucose levels stabilized, and from the day 18 of hospitalization, insulin administration compatible with the scale was no longer necessary (Fig. 2).

Figure 2.

Clinical course of the patient admitted with diabetic ketoacidosis. Cr: creatinine, CRP: C-reactive protein, CVII: continuous venous insulin infusion, TAZ/PIPC: tazobactam/piperacillin

Discussion

The treatment of schizophrenia includes first- and second-generation antipsychotics. First-generation antipsychotics often have side effects such as Parkinson's disease symptoms, including tremors, dystonia, muscle stiffness, dysarthria, and extrapyramidal symptoms, including akathisia (21). Second-generation antipsychotics have a lower risk of side effects, such as extrapyramidal disorders, than first-generation antipsychotics, and are more effective against dementia (22). Olanzapine is a second-generation antipsychotic drug classified as a Multi-Acting Receptor-Targeted Antipsychotics (MARTA) and is often the first-line drug for the treatment of schizophrenia. However, side effects, such as weight gain and glucose metabolism disorders are problematic (23). The Clinical Antipsychotic Trials of Interventional Effectiveness (CATIE) study, a large clinical trial on schizophrenia, found that olanzapine was more likely to cause weight gain and blood sugar increase than quetiapine and other atypical antipsychotics (24). In a nested case-control study evaluating the effect of olanzapine and risperidone on diabetes risk in patients with schizophrenia, olanzapine users reported a significantly higher risk of developing diabetes than non-users and patients receiving conventional antipsychotics (25).

Various mechanisms have been reported by which olanzapine causes hyperglycemia. Tecott et al. reported that inhibition of the 5-hydroxytryptamine 2c receptor in the hypothalamus stimulates appetite centers and increases appetite (26). Orthen-Gambill and Salomon reported that inhibiting histamine H1 receptors in the small intestine suppresses satiety and increases food intake (27). Murashita et al. reported that olanzapine stimulates ghrelin secretion, resulting in appetite and weight gain (28). Studies of glucose metabolism and insulin resistance have also been conducted. Olanzapine reportedly activates adenosine 5'-adenosine monophosphate-activated protein kinase (AMPK) in the hypothalamus by antagonizing central dopamine D2 receptors, histamine H1 receptors, and α1 adrenergic receptors, which in turn increases blood glucose levels by stimulating hepatic gluconeogenesis through stimulation of β2-adrenergic receptors in the liver via sympathetic nerve activation (29,30). Babkin et al. had also been reported to cause hyperglycemia due to a decrease in glucose transporters and inhibition of glucose accumulation in muscle or adipocyte cells (31). Vedal et al. reported that the Homeostatic Model Assessment for Insulin Resistance score was significantly higher in patients receiving olanzapine alone than in healthy individuals, regardless of the body mass index (BMI), and that changes in olanzapine-induced adipokine levels had an effect (32).

Thus, olanzapine-induced diabetes has been explained as weight gain associated with increased appetite, followed by insulin resistance (11-17). Atypical diabetes mellitus without obesity can also be induced, and its mechanism of action has been extensively studied (18-20). In animal experiments, the blockade of muscarinic receptors may inhibit cholinergic insulin secretion (33). The direct and indirect effects of central muscarinic M3 receptor inhibition and muscarinic M3 receptor inhibition on insulin secretion in pancreatic β-cells also cause side effects on glucose metabolism (34). Ninagawa et al. reported that olanzapine inhibits insulin secretion from pancreatic β-cells by blocking the maturation of proinsulin, an insulin precursor, leading to its degradation. In the presence of olanzapine, impairment of the intramolecular disulfide bond formation of proinsulin results in intermolecular disulfide bonding, and an appropriate structure cannot be acquired. Consequently, proteins that fail to fold correctly are retro-translocated into the cytosol and degraded by the ubiquitin-proteasome system (35).

Diabetic ketoacidosis is a severe form of hyperglycemia with acidemia, the onset of which is acute and difficult to predict. The mortality rate is estimated to be ＜1%, but the mortality rate is higher in older individuals and patients with other life-threatening diseases (36). Diabetic ketoacidosis is more common in people with type 1 diabetes than in others but occurs when a person suffers from a severe infection or other disease, binge eating, or forgetting to inject insulin. In contrast, cases of diabetic ketoacidosis due to sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported in patients with type 1 diabetes mellitus (37,38). Patients with both type 1 and type 2 diabetes mellitus can develop diabetic ketoacidosis when taking SGLT2 inhibitors (39). In the present case, there was no family history of diabetes or indication for the development of diabetes on an outpatient basis. Tests for anti-glutamic acid decarboxylase and anti-insulin antibodies were negative. In the present case, the patient's BMI was 16.3, indicating no obesity, and no overeating or weight gain occurred throughout the course.

Risk factors for the development of diabetes mellitus with atypical antipsychotics include polyphagia, obesity, and weight gain; however, there are reports of the development of diabetic ketoacidosis in patients with no risk factors (40). Henderson et al. report that patients hospitalized with diabetic ketoacidosis had very high HbA1c levels of 13.3±1.9% on average. These patients were considered to develop diabetic ketoacidosis after weeks or months without being diagnosed with diabetes, and at some points due to additional causes such as infections (41). In the present case, a long-term state of hyperglycemia may have been sustained, as dry mouth was observed for five years, the HbA1c level was remarkably high (17.6%) at the time of hospitalization, and diabetic neuropathy was observed. In addition, at the time of hospitalization, there was contamination around the urethral opening, and there had been incontinence at home before hospitalization because she could not make it to the toilet in time to urinate; therefore, diabetic ketoacidosis may have developed due to the concomitant occurrence of urethritis.

Diabetic retinopathy, nephropathy, and neuropathy are three major complications of diabetes, with diabetic neuropathy being the most common. In daily clinical practice, polyneuropathy may appear along with symptoms of sensory and autonomic neuropathy. One of the symptoms of autonomic neuropathy is known to affect the function of the bladder and urethra, i.e. the function of the lower urinary tract. Many patients are asymptomatic (42,43). Even if residual urine is present, it may be overlooked by the patient, and in advanced cases, there is no pain despite urinary retention. In women, lesions may appear as masses in the lower abdomen. In the present case, the patient had no subjective symptoms until an examination at the hospital.

In the natural history of diabetic bladder disorders, bladder dysfunction due to osmotic polyuria caused by hyperglycemia occurs during a relatively early compensatory period, and the detrusor muscle is enlarged by frequent urine collection and urination, resulting in detrusor hyperactivity. Microangiopathy and neuropathy are leading causes of systemic complications associated with diabetes. As the disease progresses, diabetic bladder disorders advance towards the decompensated stage. Insulin resistance, glucose metabolism disorders, oxidative stress, and ischemia can all lead to these conditions. Owing to a decrease in bladder perception, the bladder capacity and residual urine volume increase, resulting in hyperextension of the detrusor muscle and a further decrease in contractile force. Ultimately, diabetic bladder dysfunction exhibits a typical diabetic cystopathy phenotype (44-47). In such situations, it is difficult to stop the progression of diabetic bladder dysfunction, even with strict blood glucose control. In the present case, a catheter was placed after hospitalization, and bladder training was started after improving blood glucose levels and renal damage. However, there was little awareness of the urge to urinate, the patient was encouraged to urinate at a regular time with the catheter in place.

Urinary retention occurs when urine in the bladder cannot be drained or is extremely difficult to expel, resulting in the persistent presence of a large amount of residual urine. The causes of urinary retention include lower urinary tract obstruction, detrusor muscle contractile insufficiency, drug effects, infection or inflammation of the lower urinary tract and genitals, and neuropathic dysuria (48). Urinary retention, which may have several causes, is characterized by acute urinary retention that develops rapidly and is accompanied by bladder pain, a strong feeling of residual urine, and chronic urinary retention that is advanced and does not involve symptoms such as bladder pain. In acute urinary retention, patient distress does not improve unless the urine is drained. Chronic urinary retention has few subjective symptoms, but complications, such as renal failure, may occur. In women, various factors, including anatomical disorders, medications, surgical history, neurological disorders, infections, and psychological factors, are involved in bladder dysfunction and urinary retention. In terms of drug properties, antipsychotics are the second most common cause after nonsteroidal anti-inflammatory drugs, but their proportion is small (49). In the present case, there were no gynecological diseases, such as uterine prolapse, a history of surgery, or psychological stress. Furthermore, physical findings and a bladder echographic examination showed no bladder obstruction. Regarding the effects of the drug, the patient was taking levomepromazine and nitrazepam in addition to olanzapine, but there have been no case reports of urinary retention caused by these drugs. We attempted to remove the indwelling catheter after discontinuation of olanzapine in our patient; however, she found it difficult to urinate. Based on the above, we considered that chronic bladder dysfunction due to diabetic neuropathy was the cause of urinary retention, having been triggered by acute urethritis.

In the present case, diabetic ketoacidosis was relieved by the continuous administration of fluid replacement, insulin, and metformin, and blood glucose was stabilized without insulin administration by discontinuing oral olanzapine. There have been reports that an impaired glucose tolerance improves reversibly if the prescription is discontinued when hyperglycemia is found. However, there have also been reports of cases in which insulin treatment was required for a long time even after discontinuation (1). In the present case, the urinary C-peptide level, which indicates insulin secretion capacity at admission, was low (13.7 μg/day). However, it recovered to 105.3 μg/day after discontinuing olanzapine, suggesting that hyperglycemia caused by olanzapine was reversible.

Our patient had had diabetes for approximately five years, and the glucose and HbA1c levels were high, suggesting that she had had severe diabetes at the time of admission. However, in the absence of the involvement of lifestyle-related diseases, such as obesity and hypertension, the main reason for the onset of diabetes might have been reduced insulin secretion with olanzapine and hyperglycemia, and it is possible that insulin sensitivity persisted in peripheral tissues. Based on the recovery of urinary C-peptide levels, discontinuation of olanzapine and the release of glucotoxicity might have ameliorated the pancreatic β-cell function, allowing insulin treatment to be avoided. In addition, the presence of infectious disease is one of the factors contributing to diabetes progression. Regarding urethritis, the urethral orifice was quite contaminated, although it is difficult to attribute the inflammatory changes at the time of admission to urethritis alone. The patient's body temperature was 35.9℃, and retrograde pelvis enlargement was observed in addition to prominent bladder enlargement. These findings suggested that pyelitis may have occurred, leading to sepsis. We believe that antibiotic treatment was successful and that the treatment of the infectious disease contributed to the improvement of diabetes.

In the present case, metformin, a biguanide-based drug, was administered orally. The risk of lactic acidosis due to metformin must be considered, as this risk increases during dehydration and decreases the kidney and liver function. We corrected the dehydration state, improved the renal dysfunction, confirmed that the patient could take oral medication, and started metformin and insulin treatment. Drugs that improve insulin resistance include thiazolidines and biguanides. Thiazolidine-based drugs are generally administered to obese patients, with edema as a side effect. Because biguanides lower blood glucose levels regardless of the obesity status, metformin was selected in the present case.

However, because our patient had neuropathy as a complication of diabetes, it was assumed that she had had diabetes for a long time, necessitating continuation of oral treatment and follow-up with regular blood glucose tests. In addition, during urinary retention, when diabetic cystopathy occurs, urination management that reduces the amount of residual urine as much as possible reduces the load on the kidneys and is thought to prevent further deterioration of the bladder function. However, currently, there is no effective drug treatment to decrease detrusor contractility. In the present case, removal of the catheter was attempted during hospitalization; however, the patient found it difficult to urinate voluntarily, so the catheter was left in place. We suspected that prolonged chronic diabetic bladder dysfunction had occured, and recovery from bladder dysfunction would take some time. The patient also had schizophrenia, which made it difficult to manage her urination; therefore, leaving the catheter in place was recommended. In cases with a high degree of residual urine that exceeds the amount that can be released at a time, the only way to deal with this issue is to introduce intermittent self-catheterization.

Conclusion

We encountered a case of olanzapine-induced diabetic ketoacidosis complicated by urinary retention triggered by urethritis. Although there have been many case reports of olanzapine-induced diabetic ketoacidosis and bladder dysfunction, no case reports have been identified that led to urinary retention. There was no history of diabetes in this case; however, the incidence of new-onset diabetes during olanzapine treatment was 35% (50), suggesting the need to carefully check for diabetes in cases with olanzapine prescriptions.

Written informed consent was obtained from the patient for the publication of this article.

The authors state that they have no Conflict of Interest (COI).