This pain drives me crazy: Psychiatric symptoms in women with interstitial cystitis/bladder pain syndrome.

To identify studies dealing with the presence of psychiatric/psychological symptoms in patients with the IC/BPS, we investigated the PubMed, CINAHL and PsycLIT/PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection databases on November 7, 2023. We also used the ClinicalTrials.gov site to identify ongoing studies, using the following strategy: Condition/disease: Interstitial cystitis; Other terms: Psychological symptoms; Intervention/treatment: blank. To be included, studies had to be original and reporting the proportion of psychiatric disorders or symptoms or psychological symptoms in patients with IC/BPS. Articles ought to be published after a peer reviewing process, to explicitly provide data for psychiatric or psychological symptoms, include patients with IC/BPS and quantify their psychiatric or psychological symptoms as a group, not lumping their data along with data of patients with other conditions (in such case, studies were excluded and labelled as “no IC/BPS” and added to the studies that did not include patients with IC/BPS), nor reporting impressions with no clear data (in such case they were excluded as “no data”). When studies referred to the same sample or to an increased sample including previously analysed patients, only the study with more data (or more complete analyses) was included, with the others excluded as “overlapping” samples. Further exclusion criteria were not reporting psychiatric or psychological symptoms, labelled as “nopsysy”, a design focused on other outcomes (labelled “off-target”, which comprised both studies with an inadequate design as referred to our aims, and unfocused papers with outcomes different from those we investigated), being not related to the subject matter (“unrelated”), surveys of treating physicians or the lay public containing their opinions than data of patients ( i.e. the sample was not composed of patients, but consisted of physicians or people interviewed by the survey promoters, labelled as “survey”), other opinion papers without data, such as editorials or letters to the editor or hypotheses and qualitative studies without precise figures as to emerged themes, labelled as “opinion”, animal or in vitro studies (preclinical), labelled as “animal”, protocols of future researches with not even preliminary data, labelled as “protocol”, reviews and meta-analyses, labelled as “review” (but their reference lists were hand-searched to identify possibly eligible studies that eluded our search strategies), and obviously duplicates or corrections of a published paper already existing in a given database; overlapping records between databases were also labelled as “duplicates”. Our search strategy was ("interstitial cystitis" OR "bladder pain syndrome") AND ("mood disorder" OR depressive OR antidepressant OR depression OR depressed OR hyperthymic OR mania OR manic OR rapid cycl* OR dysthymi OR dysphori) for all databases and was carried out on November 7, 2023. To decide eligibility of a given study, we performed Delphi rounds among all authors until complete consensus was reached. Not more than three were necessary for all articles. We conducted this systematic review adopting the PRISMA statement[ 21 ]. Detailed results of databases searching, PRISMA checklist and flowchart are shown in the Supplement. Overall judgments for each rated study and comments are shown in the online Supplement ( Supplementary Table 1 ). We did not register our review on PROSPERO. The articles resulting from our search are shown in the Supplement, along with inclusion/exclusion decisions and the reasons for the latter. The selection process is depicted in Figure 1 , which shows the PRISMA flowchart. Risk of Bias (RoB) was assessed through the Cochrane RoB method as described in the Cochrane Handbook[ 22 ]. PRISMA flowchart of our search and inclusion procedures. 1 Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers); 2 If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools; 3 No automation tools were used. IC/BPS: Interstitial cystitis/bladder pain syndrome.

Our search on November 7, 2023 yielded 224 records on PubMed, 62 on CINAHL, and 36 on PsycLIT/PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection, and 1 added from other sources, for a total of 323 records, 67 of which were duplicates and immediately removed. The inclusion process is depicted in Supplementary Table 1 . Records identified by the search strategy spanned from March 1988 to October 25, 2023, with eligible records ranging from July 2000 to October 2023. There were 63 records identified as eligible; they are summarised in Table 1 [ 23 - 85 ]. These studies were longitudinal ( n = 29) or cross-sectional ( n = 34). There were some studies conducted with the same sample, but they focused on different outcomes, so we retained them all[ 35 , 36 , 49 , 54 , 55 , 60 , 70 ] (Table 1 ). Summary of studies investigating psychiatric symptoms in interstitial cystitis 1 Chronological order is maintained. ↑: Increase, augmentation, elevation, improvement; ↓: Decrease, decreased, lower, diminution, worsening; Anx: Anxiety; BAI: Beck Anxiety Inventory; BCPCI: Brief Chronic Pain Coping Inventory; BDI: Beck Depression Inventory; -II: 2 nd version; BL: Baseline; BoNT/A: Botulinum A toxin; BPI: Brief Pain Inventory; BPS: Bladder pain syndrome; BSI: Brief Symptom Inventory for somatic sensitivity; CBT: Cognitive behavioural therapy; CES-D: Center for Epidemiologic Studies Depression Scale; CFS: Chronic fatigue syndrome; COPC: Chronic overlapping pain conditions; CP: Chronic prostatitis; CPP: Chronic pelvic pain; CPPS: Chronic pelvic pain syndrome; CS: Cross-sectional; CSQ: Current Symptoms Questionnaire; CSS: central sensitivity syndromes; CTES: Childhood Traumatic Events Scale; CTRL: Controls; CUP: Chronic Urogenital Pain; DAQ: Drossman Abuse Questionnaire; dep: Depression/depressive; DD: Depressive disorder; dep: DERS: The Difficulties in Emotion Regulation Scale; DS14: Weng’s Taiwan Type-D scale; EFS: University of Washington Ejaculatory Function Scale; FD: Functional dyspepsia; FM: Fibromyalgia; FSFI: Female Sexual Functioning Inventory; FUP: Follow-up; GDS: Geriatric Depression Scale; GIQLI: Access the Gastrointestinal Quality of Life index; GQ: General Questionnaire; GRA: Global response assessment; GUPI: Genitourinary Pain Index; HA: Hyaluronic acid; HADS: Hospital Anxiety and Depression Scale; HAM-A/D: Hamilton Anxiety/Depression Rating Scales; HC(s): Healthy control(s); HL(s): Hunner lesion(s); HR: Hazard ratio; HRQOL: Health-Related Quality of Life; IBS: Irritable bowel syndrome; IC: Interstitial cystitis; ICES: Interstitial Cystitis Self-Efficacy Scale; ICPI: IC Problem Index; ICSI: IC symptom index; ID: Index date; Inj: Injection; IIEF-EF: International Index of Erectile Function-Erectile Function Domain; IPIP: International Personality Item Pool; IR: Incidence rate; IRR: Incidence rate ratio; KGDS: Korean Geriatric Depression Scale; KHQ: King's Health Questionnaire; Lo: Longitudinal design; MD: Major depression; MOS SF-12/SF-36: Medical Outcomes Study Short-Form 12/36; QoL: Quality of Life; MPQ: McGill Pain Questionnaire; SF: Short form; MSPSS: Multidimensional Scale of Perceived Social Support; Questionnaire; NHIRD: National Health Insurance Research Database; NIH-CPSI: Prostatitis Symptom Index of the National Institute of Health; ns: Not significant; OAB: Overactive Bladder; OAB-V8: Overactive Bladder Form V8; OBS: Overactive bladder syndrome; OdR(s): Odds ratio(s); PA: Panic attacks; PAS: Psychache Scale; PCS: Pain Catastrophising Scale; PDI: Pain Disability Index; PHQ-9 DM: Patient Health Questionnaire Depression Module; PHQ-9: Patient Health Questionnaire 9; PISQ-12: Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire; PROMIS: Patient-Reported Outcomes Measurement Information System Anxiety Scale; PSQI: Pittsburgh Sleep Quality Index; PSS: Perceived Stress Scale; -10: Chen’s perceived stress scale; pt(s): Patient(s); PTSD: Post-traumatic stress disorder; PUF: Pelvic Pain and Urgency/Frequency; RCT: Randomised control trial; RIISQ: Rome II standardised questionnaire; RR: Relative risk; SBQ-R: Suicidal Behaviors Questionnaire-Revised; SEAR: Self Esteem and Relationship; SF-36: 36-item Medical Outcomes Study Short Form; SF-MPQ: The Short Form–McGill Pain Questionnaire; SHS: State Hopelessness Scale; SI: Suicidal ideation; SoDi: Somatoform disorder; SRDs: Stress-related diseases; SSS: Self-Stigmatization Scale; STAI: State-Trait Anxiety Inventory; STAI-Y1: State anxiety; STAI-Y2: Trait anxiety; sym(s): Symptom(s); T : Student’s T -test; UCPPS: Urological chronic pelvic pain syndrome; UPOINT: Urinary: psychosocial: organ-specific: infection: neurogenic: and tenderness Urological Treatment Program for Chronic Prostatitis; UPS: Urological pain syndrome; VAS: Visual analogue scale. The search conducted on the ClinicalTrials.gov site provided 14 trials. Of them, 9 were interventional and 5 observational (Table 2 ). Ten were completed, one was recruiting, one was not yet recruiting, and two had an unknown status. None had data to provide or publications related with their data. However, three of them had received publication by the above date (one in a preprint, not peer-reviewed, Table 2 ). Studies emerging from searching the ClinicalTrials.gov site on the November 7, 2023. Strategy used: Condition/disease: Interstitial cystitis; Other terms: Psychological symptoms; Intervention/treatment: blank (not required) Data from ClinicalTrials.gov and internet searches. Figure 2 shows the distribution of included studies across time. An increase can be noted from early to recent years, which is not steady, but rather fluctuating. However, the 17-year 2000-2016 period provided 29 studies, less than those of the 7-year 2017-2023 period ( n = 34). Per year distribution of eligible studies. Studies were scattered though many sites worldwide, although most of them are concentrated in the United States-North America. Among the 14 ongoing or unpublished studies in the ClinicalTrials.gov database, 9 are in the United States and the United States participates in another multinational study (United Kingdom, Portugal, Germany, and Denmark). The other studies in this database are two Italian, one Turkish, and one Israeli. Among eligible studies, 31 were performed in the United States alone, two were performed conjointly with Canada, three were international studies involving Canada, Denmark, and India, while five were Canadian only studies, eleven Chinese, two French, two South Korean, two Italian, one each German, Turkish, Russian, and Dutch and one was “international” (unspecified where from, but data processed in Philadelphia, PA, United States). Surprisingly, no eligible study was based in Australia-New Zealand, and no study came from Africa, presumably for economic reasons. Initially, most studies were single-site, prevalently cross-sectional[ 23 - 26 ], and regarded patients seen vis-à-vis; later, from 2008 on, there started international collaborations and multicentre studies[ 39 , 40 , 46 , 72 ], and those accessing extensive databases[ 29 , 35 , 36 ], thus enriching the potential of identifying IC/BPS cases appropriately. Details of the assessment scales used are provided in Table 1 . There were 157 psychological research foci in the 63 eligible studies, i.e. about 2.5 foci per study. These were depression (56 studies), anxiety (31 studies), quality-of-life (QoL, 15 studies), catastrophizing (14 studies), sleep quality (9 studies), alcohol use disorder-related (4 studies, 1 also drug use disorder), perceived stress (4 studies), post-traumatic stress disorder (PTSD, 3 studies), sexual trauma (2 studies), or childhood abuse (2 studies), panic disorder (3 studies), somatoform disorders (3 studies), suicide-related issues (3 studies, one each suicidal ideation, suicidal behaviour, and psychache), general mental health (2 studies), emotional regulation (2 studies), and one study each alexithymia, dissociation, neuroticism, and psychosis. Of the 56 studies that focused on depression, 22 found definitely increased levels of depression [mostly assessed with the Hospital Anxiety and Depression Scale (HADS)[ 86 ]] in patients with IC/BPS, while 5 found associations/correlations between having depressive symptoms and severity of IC/BPS. Longitudinal studies addressing treatment of IC/BPS found either no change in existing depressive symptoms post-treatment[ 57 ] or a decrease of depression with treatment[ 78 ]. Seven of the studies that investigated anxiety symptoms found a definite increase of these symptoms in the IC/BPS population, while all studies investigating functioning or QoL found them to be both decreased and impaired in this patient population. Of note, all studies addressing catastrophizing but two[ 46 , 68 ], found either high levels to correlate with anxiety and negative affect (depression)[ 25 , 44 , 52 ] or increased levels in IC/BPS patients compared to control populations[ 50 ] and also a beneficial effect of targeted psychotherapies[ 58 , 65 ]. Studies assessing suicidality showed contrasting results. One identified suicidal thinking in all IC/BPS groups[ 51 ], another showed that suicidal thinking was prominent in an IC/BPS sample, involving more than 38% of patients (more than the SBQ-R, Suicidal Behaviors Questionnaire-Revised[ 87 ] cutoff) and was most often accompanied by perceived burdensomeness, hopelessness and psychache[ 76 ], and still another found suicidal ideation to be independent from IC/BPS symptoms or the IC/BPS condition per se , but to be possibly mediated by depression[ 41 ]. One study related suicidal ideation to catastrophising in an IC/BPS sample[ 50 ]. Similarly, traumatised patients, either with PTSD or sexual or physical abuse, were more prone to develop IC/BPS. Such patients, as expected were found to have emotional distress and/or dysregulation[ 23 , 24 , 37 , 65 , 67 ]. We may speculate that any psychological symptom one wishes to investigate in IC/BPS has a high likelihood to be found altered. Of the 63 included studies, 36 were carried out on women only, while the other 27 included patients of both sexes. This is a serious bias, since IC/BPS is found in both sexes, although they are more prevalent in women with female-to-male ratios varying from 1.6 in the United States[ 88 ] to 4 in China (Taiwan)[ 89 ]. Furthermore, it was not possible to calculate the exact number of participants in the various eligible studies, because many of them reported on the same databases through the years with variously overlapping samples (and participating sites). However, adding the figures provided in the studies involving both sexes, we obtained a female-to-male ratio of 1.034 (with total populations of 2041347 and 1974723, respectively), which is not credible, biased toward the male sex and does not match most epidemiological data.

An integrated clinical approach focusing on the patients’ emotional and psychological state and global health and personalized treatments could ensure proper symptom control and promote adequate prevention of comorbidities and future disease-related implications[ 10 ]. Thus, it would be possible to cope innovatively with a complex and disabling condition, limiting the dramatic impact on patients' QoL, self-esteem, and social functioning. Future perspectives could involve finding neuroimaging alterations in people with IC/BPS that overlap with those of established alterations in psychiatric conditions which are frequently encountered in IC/BPS. However, to be sure whether alterations precede or follow the development of IC/BPS (the egg or the chicken dilemma), entire populations should be followed with neuroimaging data and look for the clinical evolution of selected people who subsequently develop UCPPSs. Although cross-sectional studies might tell us something about the factors determining IC/BPS, the 0.85 Longitudinal/cross-sectional ratio we found here should surpass the unit in future studies, should we understand the deeper underpinnings of IC/BPS–CP/CPPS. Future research should ascertain the reciprocal causal relationships between psychiatric/psychological factors and IC/BPS–CP/CPPS symptomatology in longitudinal studies, which are the only ones that could enable us to provide a response to the egg or the chicken dilemma. In fact, the simultaneous presence of factors does not legitimize us to establish cause and effect relationships, while factors present at baseline could be related or not related to a future development of a pathological trait.

This review showed a high prevalence of IC/BPS in the human female population and a high prevalence of psychological and psychiatric symptoms. There was an imbalance between male and female patients in favour of the latter in the sample taken into consideration in the eligible studies mainly because many studies excluded males. This way it is impossible to generalise on the psychological underpinning of this condition, but we may draw conclusions that may mostly apply to affected women. IC/BPS is a condition affecting both sexes, although diagnosis is still a problem, and sex-related cultural factors may contribute to underdiagnosis in the male sex[ 90 ]. It is estimated that IC/BPS occurs between 2%-18% of the general population[ 91 ], with a female-to-male ratio oscillating between 6.5 and 12[ 92 ]. Although it is reported that there is an increased incidence of this condition, this may only be an impression[ 93 ] and is mainly based on data from some parts of the world where increased interest in searching the term on the internet[ 92 ], it is possible that this does not reflect true changes in incidence, but rather changes in diagnostic criteria and awareness (or unawareness)[ 94 - 96 ]. Diagnostic criteria differ among the various countries, so the differences reported on the prevalence of IC/BPS may depend both on how the condition is diagnosed in a specific country and on cultural or ethnicity factors and on when the study was performed. For example, a first study in Finland conducted on 960,000 people identified 95 women and 8 men with IC/BPS in 1975, i.e. a prevalence of 18.1/100000 women of all ages, while for both sexes the prevalence was 10.6/100000[ 93 ]. The incidence in this sample was 1.2/100000 women each year[ 93 ]. Twenty years later in the Netherlands another study found a prevalence of 8-16/100000 women, thus approximating the figures in the first Finnish study[ 97 ]. Meanwhile, in the United States, there were two studies, using different assessment methods and criteria, which found very different prevalence rates; one found a prevalence of 30/100000 in 1987 using mailed surveys of board certified urologists[ 94 ], the other reported a prevalence of 510/100000 in 1989 based on participants’ self-reports in 1989[ 98 ]. A second Finnish report presented data obtained through self-reports of contacted people in a representative sample and identified a prevalence rate of 450/100000[ 99 ], much higher than the preceding study, which was based on medical record examinations[ 93 ]. A third Finnish study[ 100 ] and an Austrian[ 101 ] one administered the O’Leary-Sant IC symptom index and IC problem index[ 102 ] in 2005-2007 to women; one found a clinically confirmed probable IC prevalence of 230/100000 and of possible/probable IC of 530/100000[ 100 ], while the other found an overall prevalence of 306/100000, which was higher in the middle-aged group (40-49 years of age, who had a prevalence of 464/100000)[ 101 ]. Another United States study carried out in 2005 was also based on patient surveys and diagnosed them according to two criteria: pelvic pain for at least 3 months plus urgency or frequency for at least 3 months or the preceding plus pain increasing with bladder filling and/or pain relieved by urination; the prevalence of IC/BPS according to the first criterion was 11.2% in women and 4.6% in men, and according to the second criterion 6.2% in women and 2.3% in men, respecting the “more than twice as many women affected than men” principle with both widened and restricted criteria[ 103 ]. A still further United States study conducted in 2007 identified a prevalence of ≥ 197/100000 among women and ≥ 41/100000 among men[ 104 ]. Prevalence changes when using relaxed criteria and extend cases to people perceiving pelvic pain. A Boston (Massachusetts) study reported a point prevalence of 2% (1.3% in men and double as much in women) when defining painful bladder syndrome as “pain increasing as the bladder fills and/or pain relieved by urination for at least 3 months”[ 105 ]. Using high specificity and high-sensitivity definitions, 2.70% and 6.53% of American women met symptom criteria, respectively[ 106 ]. For men, high specificity definition applied to 1.9% of the sample and high sensitivity to 4.2%[ 107 ]. In the United States, prevalence of self-reported IC and clinician-rated IC symptoms were 3.7% and 4.4%, respectively, pointing to lack of overreporting of such symptoms among women; however, expanding to women reporting only pelvic pain, the prevalence rose to 17.3%[ 108 ]. Studies from Asian countries reported data similar to those of Western countries, i.e. 0.98% in the Fuzhu, Fujian province of China, based on mailed questionnaires[ 109 ], and 0.26% in South Korea in 2011, based on a telephone survey with the administration of the O’Leary-Sant IC symptom index and IC problem index[ 110 ], but a more recent study in South Korea, conducted 10 years later, based on an online survey and computer-assisted personal interviews and using structured questionnaires, reported an alarmingly high prevalence of 16.4%, with women (21.4%) being affected at a double rate then men (10.7%)[ 111 ]. The lack of uniformly adopted criteria and cultural changes may account for the discrepancies observed. It is curious that the annual incidence was always found to be low (or slow if you prefer), but from 1975 to 2008 it went from 1.2/100000[ 93 ] to 15/100000 women[ 112 ]. How is it possible to have few cases each year and have also high total numbers of a condition? Something must be wrong with epidemiological calculations. In special settings, as expected, higher proportions of cases meet criteria for IC/BPS. In a United States primary care setting, 13.1% patients scored high enough on the Pelvic Pain and urgency/frequency questionnaire[ 113 ] to suggest probable IC; again, women (17.5%) were approximately double than men (8.3%)[ 114 ]. In Spain, out of 9312 patients of both sexes attending functional urology and urodynamics units in the first 4 mo of 2014, 5.4% ( i.e. n = 503) were diagnosed with IC/BPS, with 90% of them ( n = 453) being women[ 115 ]. Despite the higher specificity of the Spanish services for capturing cases of IC/BPS, more cases were found in the rather aspecific United States setting. Cultural differences could account for this discrepancy. Furthermore, the male-to-female ratio was smaller in Spain. Summarising, both incidence and prevalence of IC/BPS appear to be rising, but rates are far from being established, since measuring methods have not found consensus. The question whether IC/BPS triggers psychological problems or it is triggered by already existing ones could be responded to by neuroimaging studies. Some few studies focused on the neuroimaging of IC/BPS. In December 2009, the “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established and focused on various outcomes of female IC/BPS and its male counterpart, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)[ 116 ]. In 2012 there was a first animal model report[ 117 ], and by 2014, the first neuroimaging projects were set[ 118 ]. The MAPP network is based on collaboration between various North American university sites and encompasses various research focus areas, including epidemiology/phenotyping, neuroimaging/neurobiology, biomarkers, and urologic chronic pelvic pain syndrome (UCPPS) translational animal models[ 119 , 120 ]. The Network is still validating and fine-tuning its methods[ 121 ] and has already identified sources of inter-site variations among its recruiting sites in in voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) measures despite using similar apparatuses for neuroimaging[ 122 ]. The MAPP Network and other studies have identified neuroimaging correlates of IC/BPS and CP/CPPS, collectively known now as UCPPS, which some are specific to UCPPS and others may extend to other chronic pain syndromes (Table 3 )[ 47 , 123 - 140 ]. These involved both structural and functional neuroimaging, adopting 3 Tesla apparatuses and VBM, DTI, and proton magnetic resonance spectrometry ( 1 H-MRS) and functional connectivity based on fMRI. However, these studies identified only correlates through cross-sectional designs, and longitudinal follow-up studies within the Network did not focus on neuroimaging. There is need that the baseline and follow-up neuroimaging is performed and focused on changes accompanying the variations of the clinical status in order to establish causes and effects. Neuroimaging studies in urologic chronic pelvic pain syndrome, i.e. interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome and other pelvic or chronic pain conditions by year of publication These studies probably used the same sample, but one reported some pain disorder comorbidity and the other no comorbidity. Sensorimotor Network: Superior Frontal Gyrus; Superior Frontal Sulcus; Precentral Gyrus; Precentral Sulcus; Postcentral Gyrus; Postcentral Sulcus; Supramarginal Gyrus; Posterior ramus (or segment) of the lateral sulcus (or fissure); Thalamus; Superior segment of the circular sulcus of the insula; Long insular gyrus and central sulcus of the insula. Basal-Ganglia Network: Nucleus Accumbens; Putamen; Caudate Nucleus; Pallidum/Globus Pallidus. Emotion Regulation Network: Pregenual Anterior Cingulate; Subgenual Anterior Cingulate; Parahippocampal Gyrus; Hippocampus; Amygdala. Executive Control Network: Inferior Frontal Sulcus; Triangular Part of the Inferior Frontal Gyrus; Superior Frontal Gyrus; Superior Parietal Lobule. Salience Network: Anterior Mid Cingulate Cortex; Anterior segment of the circular sulcus of the insula; Inferior segment of the circular sulcus of the insula. Default Mode Network: Marginal branch (or part) of the Cingulate Sulcus; Middle Temporal Gyrus; Superior Temporal Sulcus; Superior Temporal Gyrus Precuneus; Posterior Cingulate Cortex Angular Gyrus. H-MRS: Proton magnetic resonance spectroscopy; ACC: Anterior cingulate cortex; ADC: Apparent diffusion concentration; AG: Angular gyrus of the parietal cortex; ASL: Arterial spin labelling; ATR: Anterior thalamic radiation; BL: Baseline; CP/CPPS: Chronic Prostatitis/Chronic Pelvic Pain Syndrome; CTES: Childhood Traumatic Events Scale; Cx: Cortex; DMN: Default mode network; DLPFC: Dorsolateral prefrontal cortex; DRN: Dorsal raphé nucleus; DTI: Diffusion tensor imaging; EALEs: Early adverse life events; FA: Fractional anisotropy; FC: Functional connectivity; fMRI: Functional magnetic neuroimaging; GABA: γ-aminobutyric acid; GCC: Genu Corpus Callosum; GM: Grey matter; HADS: Hospital Anxiety and Depression Scale; HCs: Healthy controls; IBS: Irritable bowel syndrome; IC/BPS: Interstitial cystitis/bladder pain syndrome; IFG: Inferior frontal gyrus; IFOF: Inferior fronto–occipital fasciculus; ILF: Inferior longitudinal fasciculus; IPL: Inferior parietal lobule; LCC: Locus cœruleus and Barrington’s nucleus complex; LPVD: Localized provoked vulvodynia; MD: Mean diffusivity; McGPQ: McGill Pain Questionnaire-Short form; MMP2: Matrix metalloproteinase-2; MMP9: Matrix metalloproteinase-2; MNI: Montréal Neurological Institute; NGAL: Neutrophil gelatinase-associated lipocalin: lipocalin-2; NMR: Nuclear magnetic resonance; OFC: Orbitofrontal cortex; PAG: Periaqueductal grey; PANAS: Positive and Negative Affect Schedule; PCC: Posterior cingulate cortex; PDM: Primary dysmenorrhea; PMC: Primary motor cortex; PoMeCx: Posterior medial cortex; Pts: Patients; PSC: Primary somatosensory cortex; rCBF: Regional cerebral blood flow; ROI: Region-of-interest; RS: Resting state; SLF: Superior longitudinal fasciculus; SMA: Supplementary motor area; SMCx: Sensorimotor cortex; SPL: Superior parietal lobule; SplCC: Splenium of the corpus callosum; SPM: Statistical Parametric Mapping; STC: Superior temporal cortex; STG: Superior temporal gyrus; SVM: Support vector machine; T: Tesla; TMJD: Temporomandibular joint dysfunction; UCPPS: Urologic chronic pelvic pain syndrome; VBM: Voxel-based morphometry; VEGF: Vascular endothelial growth factor; VMPFC: Ventromedial prefrontal cortex; WM: White matter; ↓: Decrease(d); ↑: Increase(d); →: Leads to: Show(ed). Another important issue linking chronic pain condition is the chronic pain patient’s tendency to catastrophise it. In our review we found evidence for the importance of pain catastrophising in the psychological symptoms displayed by IC/BPS–CP/CPPS patients[ 25 , 44 , 50 , 58 , 65 , 71 , 72 ]. Pain catastrophising, which is the patient’s bleak outlook about the outcome of his/her pain, is also present in other types of pain[ 141 - 144 ], and this has been shown to be related to emotional dysregulation[ 145 ]. We found the two constructs to be related also in women with IC/BPS[ 65 ]. It would be interesting to understand the neurobiological underpinnings of pain catastrophising and emotional dysregulation and whether altered brain functional connectivity matches the findings of functional connectivity alterations in UCPPS. For example, one hypothesis is that PC and pain perception is associated with reduced or higher neurotrophic factor levels [ i.e. lower urinary brain-derived neurotrophic factor (BDNF) and higher nerve growth factor and vascular endothelial growth factor, which in turn would trigger neuroinflammation][ 16 ]. It is fascinating to investigate whether psychotherapy focusing on pain catastrophising or life stress, emotional awareness, and emotional expression can reduce perceived pain in IC/BPS patients through BNF-related mechanisms. In fact, some psychotherapies have been reported to increase BDNF levels[ 146 ], which probably involves improvement in cognition, even in severely ill patients with psychosis[ 147 ]. Further steps would involve looking at which specific psychotherapy or pharmacotherapy obtains desired changes in the neurobiological signature of IC/BPS–CP/CPPS. Another issue is the effect of integrated, interdisciplinary treatment of IC/BPS compared to single treatments, like pharmacotherapy, psychotherapy or physical therapies. In fact, it was recently shown that combining cognitive behavioural therapy with as-usual bladder treatment was superior to bladder treatment alone[ 148 ]. Unfortunately, there is only one such credible study available in the literature at this moment. Further replications of this study will pave the way to appropriate multimodal treatment in IC/BPS–CP/CPPS.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic (lasting 6 mo or more) non-infectious bladder inflammation of unknown origin. The cardinal symptom is chronic suprapubic, abdominal, and/or pelvic pain. At the same time, patients may show pollakiuria, nocturia, urinary urgency, and dyspareunia[ 1 ]. Alterations in the sexual, behavioural, cognitive, and emotional domains are not uncommon[ 2 ]. Furthermore, after diagnosis, patients with IC/BPS are commonly untreated or treated for more than two-thirds of cases with drugs lacking approval from official agencies[ 3 ], thus increasing the occurrence of comorbidities and amplifying its healthcare costs. The epidemiological data reported in the literature are partly inaccurate due to a high misdiagnosis rate. However, IC/BPS seems to affect 20% of women, while being quite uncommon between men[ 3 ]. Since the aetiopathogenesis of IC/BPS is little known, its diagnosis is difficult to make and the therapeutic options are limited. Its pathophysiology is believed to involve pelvic wall defects with increased permeability of the transitional epithelium to urinary toxins and consequent transmural inflammation[ 1 ]. The initial trigger may be infectious ( Proteus mirabilis , Klebsiella pneumoniae , Citrobacter , Enterobacter , Pseudomonas , Enterococcus faecalis , Staphylococcus saprophyticus , and group B streptococci, but most of all Escherichia coli [ 4 ]) or not, and may induce aberrant immune and inflammatory responses[ 5 ]. These may result in increased production, activation and degranulation of mast cells and eosinophils, and the subsequent release of histamine and proinflammatory cytokines may ensue in inflammation, consequent vasodilation, sensory nerve stimulation and eventually, tissue damage[ 5 ]. Neurogenic inflammation and nerve fibre proliferation, with nerve hyperstimulation and sensory abnormalities[ 1 , 6 , 7 ] and recurrent urinary infections[ 1 ] may also concur. Finally, IC/BPS has been associated with early emotional trauma and hyperactivation of the stress axis[ 2 ]. The pelvic diaphragm has an extremely complex innervation that includes several neurological pathways, the function of which has not been elucidated. It is probable that this very intricate innervation is under the control of higher centres; in fact, psychological and emotional factors affect profoundly the function of the pelvic floor. It could be that pelvic organs cross-sensitize in response to earlier threat or traumatic events, prompting some investigators to add a bladder component to the brain-gut axis (including the microbiome) and speak about the bladder-gut-brain axis[ 8 ]. This cross-sensitization could result in perceived conjoint bladder- and gut-related emotional distress. Psychosocial factors, like comorbid anxiety and depression, low quality of life, and trauma-related symptoms accompany and intensify the illness[ 9 , 10 ]. While psychosocial factors influence the development of chronic pain[ 11 ], unaddressed psychosocial elements of chronic pain can in turn shape patient perceptions and behaviour, often leading to symptom persistence through central sensitization[ 12 ] and are associated with poorer functioning, adjustment, prognosis, and response to treatment[ 12 ]. These findings suggest not only a strong association, but also that psychosocial symptoms and bladder-specific symptoms reinforce one another bi-directionally. In addition, the perception of pain and its chronicity may be modified by emotional and cognitive factors[ 13 ]. Increasing evidence suggests that the tendency to magnify the threat value of the pain stimulus, the sense of helplessness in the face of pain, and the inability to inhibit pain-related thoughts, which together constitute the psychic phenomenon known as pain catastrophizing (PC), are associated with the activation of brain regions implicated in processing the affective dimensions of pain but also in cognitive regulation of emotion and cognition, such as the anterior cingulate cortex and ventromedial and dorsolateral prefrontal cortices and can lead to aberrant hypothalamic-pituitary-adrenal axis activity and altered cytokine responses to pain[ 14 ], thus resulting in maladaptive plastic changes responsible for the maintenance of chronic pain[ 13 ]. Since chronic pain is the cardinal symptom of IC/BPS, these processes could be involved in the pathophysiology of the disorder. Therefore, careful assessment of pain and PC should be included in the clinical workup of IC. In fact, PC was shown to be present in IC/BPS and constitute a core factor[ 15 , 16 ] with a bidirectional relationship[ 17 ], with its effect on IC/BPS being mediated by other psychological factors[ 18 ]. From this perspective, the poor outcomes in terms of therapeutic efficacy could be traced to inadequate care-taking[ 19 ] that underestimates psychological factors and concomitant psychiatric disturbances[ 20 ]. The aim of this review was to identify psychological and mental symptoms in IC and chronic bladder pain to underline the urgent need for integration of psychological assessment and management into care plans for IC/CBP.

The authors are grateful to the Scientific Administration of the Bibliographic and Bibliometric Support Service, Fondazione Policlinico A. Gemelli IRCCS, in particular, Dr. Maria Pattuglia, and Ms. Mimma Ariano, Ms. Ales Casciaro, Ms. Teresa Prioreschi, and Ms. Susanna Rospo, Librarians of the Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, for rendering precious bibliographical material accessible.