Depression, Anxiety and the Bladder

Authors


Correspondence: Ryuji Sakakibara, MD, PhD, Division of Neurology, Department of Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741 Japan. Tel: +81-43-462-8811 ext. 2323; Fax: +81-43-487-4246. Email: sakakibara@sakura.med.toho-u.ac.jp

Abstract

Depression and anxiety are common mental illnesses. It is recognized that depression/anxiety causes physical changes, including insomnia, anorexia, and bladder dysfunction. We aimed to delineate bladder dysfunction in patients with depression/anxiety by reviewing the literature. We performed a systematic review of the literature to identify the frequency, lower urinary tract symptoms (LUTS), urodynamic findings, putative underlying pathology, and management of bladder dysfunction in patients with depression/anxiety. From a recent survey of a depression cohort (at a psychiatry clinic), the frequency of bladder dysfunction in depression is lower (up to 25.9%) than that in Parkinson's disease (up to 75%) and stroke (up to 55%), whereas it is significantly higher than that in age-matched controls (around 10%). In both the depression cohort and the psychogenic bladder dysfunction cohort (at a urology clinic), the most common LUTS was overactive bladder (OAB), followed by difficult urination and infrequent voiding. Compared with severe LUTS, urodynamic findings were dissociated; i.e. urodynamic findings were normal except for increased bladder sensation without detrusor overactivity for OAB (50% of all patients), followed by underactive detrusor without post-void residual for difficult urination. The effectiveness of serotonergic or anti-cholinergic medication for ameliorating OAB in the patients awaits further study. In conclusion, although the frequency of LUTS among the depression cohort is not elevated, depression/anxiety is obviously a risk factor for OAB. This finding presumably reflects that the bladder is under emotional control. Amelioration of bladder dysfunction is an important target in treating patients with depression/anxiety.

1. INTRODUCTION

Major depression is a common mental illness with a prevalence of around 6% of the general population. It is characterized by feelings of sadness and despair, and causes significant morbidity.[1] Anxiety and stress-related disorders are also common, with estimations of their prevalence in the general population ranging from 2% to 20%. These disorders are characterized by excessive worry and irritability[2] mixed with symptoms of depression. It is well recognized that depression/anxiety causes not only mental but also physical changes. Physical changes associated with depression/anxiety include insomnia,[1] anorexia,[2] tachycardia,[3] sexual/erectile dysfunction,[4-6] bowel dysfunction,[7] and bladder dysfunction (mostly an overactive bladder [OAB, urinary urgency and frequency with/without urinary incontinence]).[5] [8-13] Depression is also not uncommon in patients with bladder dysfunction.[14] Recently, functional neuroimaging suggested that the bladder is under tonic influence of the brain.[15, 16] Parkinson's disease and stroke are one of the major neurologic disorders, and they also cause bladder dysfunction.[17, 18] Although the frequency of bladder dysfunction in depression is lower (up to 25.9%) than that in Parkinson's disease (up to 75%) and stroke (up to 55%), it is significantly higher than that in age-matched controls (10%).[17-19] Therefore, depression/anxiety can be regarded as an important cause of bladder dysfunction, although the detailed mechanism of the causation remains unclear. In this review, we performed a systematic review of the literature to identify the frequency, lower urinary tract symptoms, urodynamic findings, putative underlying pathology, and management of bladder dysfunction in patients with depression/anxiety.

2. LOWER URINARY TRACT SYMPTOM IN DEPRESSION/ANXIETY

2.1. From a depression cohort

Although lower urinary tract symptoms (LUTS) have been described in major depression,[6-8] ,[11-13], [20] it is difficult to determine to what extent depression is a contributing factor. Lower urinary tract symptoms are common in the general population.[21] Men aged 60 or older may have benign prostatic hyperplasia.[22] Women may have physical stress-induced urinary incontinence. In addition, neurologic diseases might contribute to LUTS. For instance, OAB occurs in persons older than 65 due, in part, to latent brain ischemia.[23] Peripheral factors for LUTS include metabolic syndrome, diabetes, dyslipidemia, hypertension, and smoking, all of which are relevant to atherosclerosis.[24, 25] To overcome these problems, patient recruitment with no selective bias, together with community-based control subjects, is needed. In a recent study by Ito et al.[19] 224 depressive patients (97 men and 127 women, aged 42 [14–80] years, illness duration 2.2 years [1 week to 40 years], all visiting a university psychiatry clinic) and 391 healthy control subjects (271 men and 120 women, age 48 [30–69] years, all undergoing an annual health survey) were recruited. The 224 depressive patients were subdivided into 128 patients who had not received any medication (drug-naïve group; 61 men, 67 women; age 40.3 [14–80] years, illness duration 1.7 [1 week to 40 years] years), and 96 patients who were referred from primary care physicians and had already received medication (medicated group; 36 men, 60 women; age 43.5 [15–79] years; illness duration 2.8 [1 week to 15 years] years). The results of the study showed that the LUTS questionnaire scores of the drug-naïve depression group (up to 25.9%) were significantly higher (P < 0.01, 0.05) than that in the control group around 10% (Fig. 1) (medicated group appears later). The majority of the depressive patients experienced the onset of LUTS at around the same time, either with or after the appearance of an affective disorder. None had a history of pelvic organ surgery, or symptoms of neurologic disorder such as stroke, Parkinson's disease or diabetes. Therefore, these symptoms could be attributed to major depression.

Figure 1.

Bladder function in control, drug-naïve depression, and medicated depression groups. Upper panel, female; lower pane, male; dark hatched, severe (always, > once a day; daytime frequency > 10 times; night-time frequency > 3 times); light hatched, mild (sometimes, > once a week; daytime frequency > 8 times; night-time frequency > twice).

Cited from Ito et al. 2012.[19]

Looking closely at LUTS, as compared with the control subjects, the drug-naïve depressive patients had significantly more cases of urinary urgency (20.9% of women; 25.9% of men), nighttime frequency (15.2, 30.0%), urinary incontinence (9.1% women); retardation in initiating urination (13.1% men), prolongation/weak stream (23.0% men), intermittency (9.8% men), and sensation of residuals (12.1, 19.7%) P < 0.01, 0.05 (Fig. 1). The quality of life (QOL) index for the drug-naïve, depressive patients was also significantly higher (9.5, 8.3%). Therefore, both storage and evacuation symptoms are common; however, among these, OAB is the most striking feature of LUTS in major depression.

A comparison of age (those 49 years old and under and those 50 years old and over) in the control group showed higher incidence of bladder dysfunction with age (without significance). In the depressive patients nighttime frequency, prolongation/weak stream (P < 0.01), urinary urgency, incontinence (P < 0.05), and QOL disturbance (P < 0.01) were more common in older patients. A comparison of sex in the control group showed nighttime frequency to be more common in men (P < 0.05). In the depressive patients, nighttime frequency and retardation in initiating urination (p < 0.05) were more common in men. A comparison of disease duration showed no difference for any category of bladder dysfunction.

Considering the effect of previous antidepressant treatment, no difference was found in the frequency of urinary urgency or delayed start between the drug-naïve group and the medicated group, who were taking tricyclic antidepressants (imipramine hydrochloride, amoxapine, etc.), tetracyclic antidepressants (mianserin hydrochloride, etc.), selective serotonin reuptake inhibitors (SSRIs) (paroxetine hydrochloride, fluvoxamine maleate, etc.), serotonin noradrenaline reuptake inhibitors (SNRI) (milnacipran hydrochloride, etc.), and others (benzodiazepine derivative, etc.).

2.2. From a psychogenic bladder dysfunction cohort

Among patients visiting urology clinics because of LUTS, psychogenic bladder dysfunction (PUD) has been well documented, and includes symptoms of OAB and voiding difficulty/retention (also called paruresis[26] or bashful bladder syndrome).[27] We reported on 16 PUD patients in a previous study.[28] The age of this previous study sample was relatively young (mean 37 years [15–69 years]), which is almost the same as that in the depression cohort described above (mean 42 years). The sex ratio was female dominant (6 men to 10 women). All of these features were consistent with previous findings.[29, 30] The most common precipitating factors to trigger LUTS were traffic accidents in three cases (in two cases, LUTS appeared just after the accident; in the other LUTS appeared 3 months after the accident) and an inability to cope with families in three cases, followed by divorcing parents in two cases. Among the precipitating factors, traffic accidents are well known to produce somatoform/conversion disorder. The final diagnoses of the patients were somatoform/conversion disorder in six, anxiety disorder in four, and depression and other mental illnesses[28] (Table 1).

Table 1. Patients with psychogenic bladder dysfunction (A)
No.PtAge (years)SexFinal diagnosisDuration (years)BackgroundOutstanding featuresCognitive disorderNeurological examinationImaging/other investigations
  1. LUTS, lower urinary tract symptoms; MMSE, mini-mental state examination (normal > 24); MRI, magnetic resonance imaging; NCS, nerve conduction study of the extremities; SSR, sympathetic sweat response; SFR, sympathetic flow response.

  2. Cited from Sakakibara et al. 2007.[28]

1MA15FHypochondria, physical stress incontinence1.5LUTS appeared 4 months after traffic accident; mother convinced the accident caused her daughter's incontinenceNoneNoneNormalLumbar MRI, pad test, laboratory examination: normal
2TM16MAutism, mental retardation1Staying indoors, abulia, not going to toiletNoneMental retardationNormalBrain MRI, laboratory examination: normal
3KK20MAnxiety disorder1.5UnknownNoneNoneNormalLumbar MRI, laboratory examination: normal
4TS21MObsession disorder1Parents divorced, strict mother; worm phobia, bullied, staying indoors, suicide attemptInsomnia, obsessive hand washingNoneNormal except for night blindBrain MRI: cerebellar arachnoid cyst, retinal degeneration, laboratory examination: normal
5KY23MAnxiety disorder1UnknownNoneNoneNormalLaboratory examination: normal
6HS24FPanic disorder4Parents divorced, quarreling with stepfather; presenting initially with retentionNoneNoneNormalLumbar MRI/ myelography, NCS, laboratory examination: normal
7MS29FConversion disorder8UnknownAbnormal wet sensation in the lower half of bodyNoneNormalGynecological examination, thermography, SSR, SFR, pad test, indigocarmine test, laboratory examination: normal
8NY29MDepression2Mother having depressionNone (communication difficult)Presumably noneNormalLaboratory examination: normal
9RK31FAnxiety disorder1Enuresis until 10 years; dental technician; quarreling with husband, separation, no childrenFatigueNoneNormalLaboratory examination: normal
10KT38FConversion disorder4LUTS appeared immediately after traffic accident, still on lawsuitLeft shoulder involuntary movement, patchy dysesthesia in the face/bodyNoneNormal except for involuntary movementBrain/cervical MRI, NCS, SEP, EEG, nEMG, laboratory examination: normal
11MK50FConversion disorder> 7Parents having industrial organic mercury poisoning in Minamata, JapanLeft side body weakness, numbness in the extremities, wheel chairNoneNormalBrain/cervical MRI, LP, NCS, laboratory examination: normal
12SN51FConversion disorder in urination, physical stress incontinence1LUTS appeared immediately after traffic accidentNoneNoneNormalCervical X ray: mild spondylosis at C5/6, lumbar X ray, laboratory examination: normal
13HJ59FConversion disorder0.2UnknownNumbness in the extremitiesNoneNormalLaboratory examination: normal
14MY59MAnxiety disorder2UnknownInsomniaNoneNormalBrain MRI, laboratory examination: normal
15SF64FConversion disorder2UnknownAbnormal explosive feeling in the mouth, trunk, abdomen, buttock; refusal to sit; afterwards, wheel chairNoneNormalBrain/cervical/lumbar MRI, laboratory examination: normal
16TI69FSenile psychosis2Home aloneInsomnia, headache, shoulder pain, appetite loss, hallucination, behavioral disorder (throwing trash from windows)Cognitive impairment (MMSE 21/30)NormalBrain MRI, laboratory examination: normal

The LUTS in the 16 PUD patients included OAB alone in five, difficult urination alone in one, and both OAB and difficult urination in 10 (Table 2). In most patients, there was a dissociation between LUTS in their daily life and urodynamic findings (Tables 2 and 3) as described below. Lower urinary tract symptoms often occurred only in particular situations. For example, in one case (case 5), OAB occurred only when the patient was riding on a train with many people standing in the aisle. The psychodynamics underlying these patients may well be reproduced by healthy individuals under stressful conditions in daily life, e.g. a person may need to use the toilet just before starting an important presentation[26] or have difficulty urinating when in close proximity to another person.[26, 31] The severity of such a phenomenon is usually mild and the duration is short. However, if an individual feels such symptoms are an extreme bother, he or she may have hypochondria or a phobia involving toileting (mental disorder caused by toileting); or, if the symptoms are severe and chronic, the individual has PUD (bladder dysfunction caused by mental disorder). Both conditions could occur together.

Table 2. Patients with psychogenic bladder dysfunction (B)
No.PatientLower urinary tract symptomQuality of life indexBowel movementQuality of life indexSexual functionQuality of life index
Urinary incontinenceUrinary urgency/frequencyDifficult urinationOthers
TypeFrequencyVolumeFrequencyType and frequency
  1. Quality-of-life index, 0, satisfied; 1, mildly dissatisfied; 2, moderately dissatisfied; 3, severely dissatisfied.

  2. Cited from Sakakibara et al. 2007.[28]

1MAPhysical stress/unwittingWeekly, but daytime aloneMinimum21/1 day1Not applicable
2TMOverflow, due to holding urineDailyLargeInfrequent voider (1 to 2 times only when forced by parents)3Not answeredNot answered
3KK22 times, but daytime aloneRetardation, prolongation, straining; daily31/1 day0None0
4TSRetardation, prolongation, intermittency, straining; dailyInfrequent voider (less than three times a day)31/2 days0Erectile dysfunction2
5KYDaytime alone, only on walking to the station/on the train31/1 day0None0
6HSNine times, but daytime aloneRetardation, prolongation, intermittency, sensation of residual; daily31/2 days0Not applicable
7MSUnwittingDaily, but daytime aloneModerateUrgency, weekly21/1 day1Not applicable
8NYUrge/enuresisWeeklyModerate22 times, daytime; seven times, nighttimeProlongation, intermittency, straining, sensation of residual; daily31/4 days1None0
9RKUrge/enuresisMonthlyMinimum10 times, daytime; three times, night-time2Not answeredNot applicable
10KTUnwittingDailyLittle13 times, daytime; three times, night-timeRetardation, prolongation, intermittency; daily11/7 days1Not applicable
11MKUrgeWeeklyLittleUrgency, weeklyRetardation, prolongation, intermittency, straining, sensation of residual; weekly2Not answeredNot applicable
12SNMixedDailyModerate11 times, daytime31/1 day0Not applicable
13HJUrgency, dailyRetardation, prolongation, intermittency, straining, sensation of residual; daily2Not answeredNot applicable
14MYThree times, night-timeRetardation, prolongation, intermittency, straining, sensation of residual; daily21/1 day0None0
15SFUrgeDailyModerate12 times, daytime; four times, night-timeRetardation, prolongation, intermittency, straining; daily3Not answeredNot applicable
16TIThree times, night-time1Not answeredNot applicable
Table 3. Urodynamic study findings in patients with psychogenic bladder dysfunction
No.PatientFree flowmetryPost-void Residual (mL)EMG-cystometryPressure-flow studySphincter EMGCRDTreatment
Volume (mL)Qmax (mL/sec)Qave (mL/sec)First sensation (mL)Bladder capacity (mL)Urethral obstructionBladder contractilityNeurogenic MUP
  1. np, not performed; Qmax, maximum urinary flow rate; Qave, average urinary flow rate; hatched area, increased sensation, e.g., volume less than normal value (first sensation, 100 < normal < 300; bladder capacity, 200 < normal < 600). Urethral obstruction (Schäfer): grade 0, normal; grade 2, equivocal; grade 3 < , obstruction (a larger number indicates more severe obstruction); CRD, complex repetitive discharge; MUP, motor unit potentials.

  2. Cited from Sakakibara et al. 2007.[28]

1MA3012501303502Normalnp
2TMnp030400No flowAcontractile detrusornp
3KKnp30652401NormalNormalNoneDiazepam
4TSnp0270500No flowAcontractile detrusorNormalNoneUrapidil; zopiclone, bromazepam; keen to use balloon catheter though no residuals
5KY1008501223202NormalnpDiazepam
6HSnp2050450No flowUnderactive detrusorNormalNone (urethra)Urapidil
7MSnp0280490npNormalnp
8NYnp8?6582StrongnpFlunitrazepam, etizolam
9RK40022185350npNormalnpImipramine, lofrazepate
10KT23534026426No flowUnderactive detrusornpRefused treatment
11MK50845502400NormalNormalNone
12SN370331450206800Normalnp
13HJ17030151080300No flowAcontractile detrusorNormalNone (urethra)Imipramine, diazepam
14MYnp  0200300npNormalnp
15SF100117101704981NormalnpFlutoprazepam, tiapride, olanzapine
16TInp  0100180npNormalnpMianserin, etizolam, tiapride

In addition to OAB and difficult urination, two of our patients also showed extremely infrequent voiding (once or twice a day) cases 2, 4 or even an unwillingness to use the toilet. Similar episodes have been described before.[32] Toileting phobia has been reported to underlie this condition, originating from previous pain in micturition as a result of a urinary tract infection[33] or painful urological investigations.[32] However, no such histories were obtained in our patients.

3. URODYNAMIC FINDINGS IN DEPRESSION/ANXIETY

Since there were no urodynamic data available in the depression cohort, we discuss those in PUD patients who visited a urodynamic laboratory because of LUTS.

3.1. From a PUD cohort

The diagnosis of PUD is basically exclusionary, particularly from urologic, gynecologic, and neurologic causes, and this disorder accompanies more obvious mental features.[29, 34] Within this context, neurologic diseases are not always easy to diagnose, since they may present with LUT dysfunction as the sole initial manifestation, as seen in tethered cord syndrome/spina bifida occulta and multiple system atrophy. In our study, the incidence rate of PUD was 0.7% (16 cases) of 2300 urodynamic cases,[28] after carefully excluding other causes by means of history (with relevant neurologic, urologic, gynecologic, traumatic, or other specific history), neurological examination and, where applicable, electrophysiology, sphincter electromyography (EMG), and magnetic resonance imaging (MRI). The prevalence rate was almost the same as those reported in studies with similar sample sizes, e.g. 2% among 1015 urodynamic cases,[30] 2.7% among 1300 urodynamic cases,[33] and 2.9% among 103 women with acute retention in a mid-sized British city.[35] As we discussed above, depression/anxiety is common in the general population, and approximately one-fourth of patients are supposed to have LUTS. However, in light of these studies, PUD patients who visit a clinic and seek further investigation are much less common.

Compared with the severe LUTS of PUD patients, the urodynamic findings were dissociated. For example, in a study by Sakakibara et al. urodynamic findings were normal except for the following.[28] The major urodynamic abnormality in the PUD patients with OAB was increased bladder sensation without detrusor (bladder) overactivity (DO) or low-compliance detrusor, which was noted in 50% of all patients (Table 3). The major urodynamic abnormality in PUD patients with difficulty urinating was underactive/acontractile detrusor, which was noted in 31% of patients. None of the patients had detrusor-sphincter dyssynergia (DSD). Most patients had more obvious mental disorders in addition to LUTS. However, in one patient (case 12), LUTS was the sole initial presentation; it was considered to be a conversion disorder in the bladder (combined with physical stress incontinence). There were three reasons for this decision: her urinary dysfunction appeared just after a traffic accident, her LUTS was dissociated from urodynamic findings, and other potential causes (including urologic/neurologic causes) were carefully excluded.

Dissociation between a patient's complaint and somatic/laboratory findings is a general feature of somatoform/conversion disorder.[29] Increased bladder sensation is clinically relevant to the OAB of patients with PUD or interstitial cystitis[36] as well as in a small proportion of neurologic patients, such as those with diabetic neuropathy.[37] Despite the relative lack of urodynamic literature concerning psychogenic OAB, Macaulay et al.[38] showed higher incidences of anxiety, depression, and phobia in patients with increased bladder sensation than in those with physical stress incontinence.

3.2. Differential diagnosis

We still do not know to what extent depression/anxiety might cause urodynamic abnormalities. Previously, the concept of “PUD” included non-situational, long-standing retentions in any environment that might require catheterization for bladder emptying. These “psychogenic” reports have shown almost all types of urodynamic abnormalities, e.g. DO[29, 39, 40] and low-compliance detrusor[29, 41] during bladder filling; and poor flow, large post-void residual, vesicoureteral reflux,[29, 40] underactive/acontractile detrusor,[29, 40] intermittent contraction,[30] and pseudo-DSD[29, 40, 42, 43] during voiding. However, as mentioned above, after carefully excluding organic causes, many PUD patients showed increased bladder sensation during bladder filling or underactive/acontractile detrusor during voiding. Otherwise, none of the patients had DO or DSD.

There were still several patients with urinary dysfunction of undetermined etiology. Some of them exhibited slight neurotic features, presumably secondary to their LUTS per se. These disorders may present with urinary dysfunction as the sole initial manifestation of possible neurogenic/myopathic origin. One such male patient turned out to have multiple system atrophy. In children and young adults, tethered cord syndrome/spina bifida occulta should be considered since bladder dysfunction can be the sole initial manifestation of this disorder.[44] Ochoa's urofacial syndrome should be considered, since this disease has been separated historically from “psychogenic” patients.[45] Ochoa's urofacial syndrome occurs in boys and girls with a peculiar smile. Bladder dysfunction is similar to that in Hinman's cases. A gene was mapped to chromosome 10q23-q24 encoding heparanase 2 (HPSE2),[46] which seems to be involved in normal development, angiogenesis and cancer metastasis.[47] Fowler's syndrome should also be considered, since this disease has been separated historically from “psychogenic” patients.[48] Fowler's syndrome occurs in young women, with a relatively high association with polycystic ovary. Sphincter hypertonicity with “whale noise” is the characteristic feature of this disorder.[49] Therefore, even in cases suggestive of depression/anxiety, a non-PUD pathology behind the symptoms should always be explored.

4. UNDERLYING PATHOLOGY OF BLADDER DYSFUNCTION IN DEPRESSION/ANXIETY

4.1. Psychosomatic aspect of bladder dysfunction

Physical changes caused by depression/anxiety are referred to as somatoform disorder (also called hysterical neurosis/conversion disorder).[50] Somatoform disorder is generally regarded as a neurologic symptom that cannot be attributed to an organic disease but arises from unconscious psychological stress. Patients with somatoform disorder present with almost all types of neurologic symptoms, e.g. disturbances of motor, somatosensory, special sensory (visual, auditory), cognitive (amnesia, aphasia, dementia, spatial neglect), consciousness, or autonomic (bladder, bowel, sexual, etc.) functions. Among these, somatoform disorder of the bladder may have specific psychodynamics; e.g. behaviors related to the bladder are highly personal and are socio-psychologically concealed.

4.2. Brain mechanism of bladder dysfunction due to depression/anxiety

The most striking feature of bladder dysfunction in depression/anxiety was OAB. Urodynamics in those patients showed increased bladder sensation, and to a lesser extent, underactive bladder without post-void residual.[28] Increased bladder sensation most probably reflects depression/anxiety, in which biological changes do occur, particularly in brain areas associated with emotion (amygdala, hippocampus, hypothalamus, and medial prefrontal cortices). A positron emission tomography (PET) study showed decreased gamma-aminobutyric acid (GABA)-A/benzodiazepine receptor bindings in the right orbitofrontal cortex and insula of unmedicated patients with panic disorder.[51] Benzodiazepine is a mainstay in the treatment of panic and anxiety disorders, whereas micturition is under tonic inhibition of GABA.[15, 16, 52] Another PET study showed decreased 5-hydroxytryptamine (5-HT, serotonin) 1A-receptor bindings in the cingulate cortex and raphe in panic disorder patients.[53] Serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), are widely used to treat panic disorder and depression, and ameliorated OAB in selected patients.[54] These drugs are thought to act on both efferent and afferent fibers from the bladder. On the other hand, brain corticotropin-releasing factor (CRF) has anxiogenic effects and increases bladder sensation.[55] Irritable bowel syndrome is highly prevalent in anxiety and mood disorders, and CRF receptor antagonists could ameliorate increased bowel sensation in those patients.[56] These findings suggest that increased bladder sensation can be a reflection of biological changes in both the emotion and micturition circuits within the brain.

In contrast, the emotional mechanism underlying the underactive/acontractile detrusor is not well understood. Neurogenic cases such as brain tumor and stroke[57, 58] and functional imaging studies[15, 16] have suggested that the cingulate cortex and insular cortex are the key areas for the generation of micturition impulses, which are sent to the brainstem structures. Therefore, functional changes in these areas might also occur in depressive/anxious patients with bladder dysfunction.

In somatoform disorders other than autonomic, functional neuroimaging studies have shown a decrease in the activity of frontal and subcortical circuits involved in motor control, and increases in the activities of supplementary motor area and midline regions for hysterical motor paralysis.[59-61] However, in somatoform disorder of the bladder, no functional neuroimaging studies are available.

5. MANAGEMENT OF BLADDER DYSFUNCTION IN DEPRESSION/ANXIETY

5.1. Serotonergic, GABAergic drugs and the bladder

Serotonergic and GABAergic drugs are the mainstay in the treatment of depression/anxiety. What is the effect of these drugs on the bladder function? Central serotonergic neurons participate in a variety of physiological functions. Recent evidence has shown that centrally administered serotonin has modulatory effects on bladder function, the main actions of which are facilitation of urine storage.[52, 62] While inhibiting the bladder, serotonin facilitates sacral anterior horn cells innervating the urethra, presumably via inhibitory interneurons, leading to urethral contraction.[52, 63] Most central serotonin is physiologically released from nerve terminals of the brainstem raphe nucleus. There is a variety of micturition-related neuronal activity in the raphe nucleus, and microstimulation has been shown to elicit inhibition of the bladder.[64] This effect might be due to activation of the raphe-spinal descending pathways, which in turn suppresses the sacral preganglionic neurons via inhibitory serotonin 1A receptors; it might also be due to suppression of the sensory afferent in the spinal posterior horn.[64]

In contrast, clinical serotonergic drugs, which may act at all seven types of serotonergic receptors, have led to a complex behavior. There is no prospective study to see whether antidepressants would ameliorate both depression/anxiety and OAB. It is reported that duloxetine (an SNRI) benefited women with stress urinary incontinence.[65] Also, well-known adverse events by SSRI[66] and SNRI[67] include urinary retention. In contrast, venlafaxine (an SNRI) increased micturition frequency and lessened post-void residual volume.[68] In a larger study among women with self-reported depression, the use of serotonergic antidepressants was statistically associated with urinary incontinence, although it is unclear whether this was secondary to larger post-void residuals.[13] In a study by Ito et al.[19] previous antidepressant treatment did not significantly affect the frequency of urinary urgency or delayed start between the drug-naïve group and the medicated group, who were taking tricyclic antidepressants, tetracyclic antidepressants, SSRIs, SNRIs and others. A recent study by Sakakibara et al. showed that SNRIs, but not SSRIs, ameliorated OAB of various etiologies.[54] Taken together, when we first see patients with both depression/anxiety and OAB, prescribing an SNRI (or other antidepressants and benzodiazepines) might be a good choice.

5.2. Anticholinergic drugs and the bladder

If the first line treatment for depression/anxiety (serotonergic and other drugs) fails to ameliorate OAB, addition of anticholinergic drugs such as oxybutynin, propiverine, tolterodine, solifenacin, and imidafenacin is an option, although no systematic data on the use of anticholinergics for OAB in depression/anxiety are available. In elderly patients with depression/anxiety, the use of medications with anticholinergic side-effects is of concern, particularly when there is a risk of exacerbating cognitive impairment. Crossing the blood–brain barrier (BBB), they can act at the M1-muscarinic receptors in the cerebral cortex and hippocampus, or M4-receptors in the basal ganglia. Factors predisposing patients to cognitive side-effects include (i) central muscarinic receptor affinity, e.g. high M1-receptor selectivity; and (ii) permeability across the BBB: size, lipid solubility, fewer hydrogen bonds, neutral or low degree of ionization and a small number of rotatable bonds.[69, 70] Darifenacin is an M3-selective antagonist and thus has less marked cognitive side-effects while trospium, a quaternary amine, has high polarity and therefore poor permeability across the BBB. Other anticholinergic side-effects include dryness of the mouth (M3) and constipation (M2,3), the latter being common in serotonergic drug use. Extended-release formulations may lessen these adverse effects.[71] Mirabeglon, a novel adrenergic beta-3 receptor agonist, seems to be promising for lessening DO with fewer central side-effects.[72]

Finally, it is known that Parkinson's disease, a common neurodegenerative disease, results in a depletion of not only brain dopamine but also serotonin,[73] and patients with this disease show both depression and OAB. Therefore, further clinical studies could be carried out in light of the current findings.

6. CONCLUSIONS

This paper reviewed current concepts of bladder dysfunction due to depression/anxiety, e.g. the frequency, lower urinary tract symptoms, urodynamic findings, putative underlying pathology, and management. Bladder dysfunction in depression/anxiety presumably reflects that the bladder is under emotional control. Although the frequency of LUTS among depression cohorts is not elevated, depression/anxiety is obviously a risk factor for bladder dysfunction; therefore, depression/anxiety should be listed in the differential diagnosis of OAB and other bladder dysfunctions. Although the degree of dissatisfaction is modest, clearly some patients need medical care for their bladder dysfunction. Amelioration of bladder dysfunction is therefore an important target in treating patients with depression/anxiety.

Acknowledgments

None of authors have financial support relevant to this study.

Disclosure

The authors declare no conflicts of interest.

Ancillary