INDEX
1. Summary p 3
2. Introduction p 4
3. Epidemiology p 5
4. Psychiatric comorbidities in IBS p 6
5. Pathopysiologic Mechanism p 8
5.1. Stress and Brain-gut axis p 8
5.2 The immune system p 10
5.3 The Microbiota-brain axis p 11
5.4 Serotoninergic System p 13
5.4 a. SERT Poymorphism in IBS p 15
5.4 b. SERT in psychiatric disorders p 17
6. Therapeutic strategy in IBS p 20
7. Aim of the study p 23
8. Study design p 23
9. Instruments p 25
9.1. Gastrointestinal assessment p 25
9.2. Psychometrics and quality of life assessment p 26
9.3. Genetic analysis polymorfism 5HTTLPR p 29
10. Statystical Analysis p 31
11. Results p 32
11.2. Longitudinal Analysis p 36
12. Discussion p 39
13. Conclusions p 42
14. Tables p 43
15. Figure p 68
16. References p 74
1. Summary
Irritable Bowel Syndrome (IBS) is the most common functional gastrointestinal (GI) disorder observed in patients who visit general practitioners for GI-related complaints. A high prevalence of psychiatric comorbidities, particularly anxiety and depressive disorders, has been reported in patients with IBS, suggesting that this association should always be considered in this setting.
In order to better define the relationship between IBS and psychiatric disorders, one hundred and fifty subjects with diagnosis of IBS and relative sub-classification (constipated, diarrhea and alternating bowel) were assessed for gastrointestinal and mental functioning at the Gastroenterological Department of University of Pisa. Over half of the subjects in the sample (56%) showed “psychopathological features” (term that covers both Axis I diagnosis both previous or current drug / psychological treatment). In this group GI symptoms severity was higher and quality of life more unsatisfactory than in the group without any psychiatric implications (44%).
Second objective of the study was to examine the efficacy of SSRI (paroxetine) in IBS patients. With the limit due to small sample size of IBS patients suitable for treatment, paroxetine showed a significant improvement not only at psychiatric but also at GI evaluations. Moreover, efficacy on abdominal symptoms was independent by the presence of psychopathological features or by quality of life and satisfaction. Consequently this study emphasizes the importance of the assessment of all IBS subjects for clear or subclinical psychiatric comorbidities that are suggestive to correlate with the severity of GI symptoms and functional impairment.
2. Introduction
The functional gastrointestinal disorders are characterized by a variable combination of chronic/relapsing symptoms that are not explained by structural or biochemical abnormalities. To date, in the absence of biological and/or instrumental "markers" clearly identifiable, the diagnosis is based only on clinical presentation.
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, with the prevalence ranging from 1.1% to 29.2% in the general population.
IBS is characterized by presence of abdominal pain or discomfort associated with altered bowel habits. Three main subtypes have been diagnsoed depending on clinical presentation: IBS predominant constipation (C-IBS), IBS predominant diarrhea (D-IBS) and IBS with mixed features of both diarrhea as well as constipation (M-IBS).
Has been reported that patients with IBS have impaired quality of life, which is more severe than in subject with structural abnormalities such as peptic ulcer and liver disease (Talley, Weaver, & Zinsmeister, 1995). In addition, IBS results in a significant use of medication, specialists consultation and emergency care (Gunn, Cavin, & Mansfield, 2003). It is estimated that in the USA the annual cost of this syndrome was approximately 1.7 billion dollars (Sandler et al., 2002).
IBS symptoms are often exacerbated during stressful events and the psychiatric treatment has a positive effect on GI symptomatology. The comorbidity of IBS with psychiatric disorder, particularly anxiety and depression, has been extensively studied but the pathophysiology and underlying mechanisms of these relationship remain actually unclear.
Traditionally IBS is considered as a combination of multiple factors including bowel hypersensitivity, altered motility, inflammation and stress.
The most important underlying mechanism that has been been claimed is the dysregulations along the “Gut–Brain axis” (D. Y. Kim & Camilleri, 2000).
Serotonin (5-hydroxytryptamine,5-HT) function seems to be involved in pathophysiology of IBS. 5-HT is not only a neurotrasmitter that modulates physiological and behavioural processes in the brain but also a key factor in the enteric nervous system (Atkinson, Lockhart, Whorwell, Keevil, & Houghton, 2006; Berger, Gray, & Roth, 2009; Cremon et al., 2011; D. Y. Kim & Camilleri, 2000). Although the physiological role of 5-HT in the gastrointestinal (GI) tract is complex and not completely elucidated, serotonin has been shown to be involved in the regulation of secretion, motility and perception in the gut. More recently, several studies have tried to link single-nucleotide polymorphisms (SNPs) of the serotonin reuptake transporter (SERT) to IBS but there is little evidence that these SNPs are functional.
3. Epidemiology
Females are affected twice respected to males (Hungin, Whorwell, Tack, & Mearin, 2003; Longstreth et al., 2006; Lovell & Ford, 2012; H. R. Mertz, 2003). IBS results more common between 20 and 40 years (Canavan, West, & Card, 2014). Caucasians show a higher prevalence than African-Americans (Minocha, Chad, Do, & Johnson, 2006).
IBS represents approximately a quarter of outpatient gastroenterology consultations (Drossman, Camilleri, Mayer, & Whitehead, 2002). Generally a large amount of patients with IBS attend to primary care in considerably different percentage through european countries. The highest proportion is in Italy (50%); 30% consult in the Netherlands, 20% in Belgium, and 10% in Switzerland, France, and Spain (Okeke et
al., 2009). These differences may again reflect diagnostic criteria employed, perceived acceptability of symptoms, and ease of access to primary care, which varies across different health care systems.
4. Psychiatric comorbidities in IBS
Bidirectional comorbidities between psychiatric illness and IBS are common. Studies have shown that from 50% to 90% of patients in treatment for IBS have current or past psychiatric comorbidity, most commonly mood and anxiety disorder (Garakani et al., 2003; Lydiard & Falsetti, 1999; Whitehead, Palsson, & Jones, 2002). It has been suggested that psychiatric comorbidity is specific to those with IBS who seek treatment, but data now indicate that the association of depressive and anxiety disorders is independent of treatment-seeking status (S. Berman et al., 2000; Mayer, Craske, & Naliboff, 2001).
Additionally, IBS patients have been shown to have features associated with depres- sion and anxiety, including high rates of psychosocial stress (Dancey, Taghavi, & Fox, 1998; Folks, 2004; Reilly, Baker, Rhodes, & Salmon, 1999), frequent trauma and abuse history (Reilly, Baker, Rhodes, & Salmon, 1999; (Drossman et al., 1990; Talley, Fett, & Zinsmeister, 1995), high prevalence of depressive and anxiety disorders in family history (Sullivan, Jenkins, & Blewett, 1995), common heritability (Hudson et al., 2003) and response to antidepressant medication (Akehurst & Kaltenthaler, 2001; Jailwala, Imperiale, & Kroenke, 2000). These shared characteristics between IBS and depression/anxiety as well as potentially shared pathophysiology have led authors to group IBS and other functional physical ailments (including chronic fatigue syndrome, migraine, fibromyalgia, and atypical facial pain) into “affective spectrum disorder” (Hudson & Pope, 1994).
Recently, has been reported that in as much as 50% of the IBS patients, an anxiety disorder is diagnosed and in 20% a mood disorder (Kruimel et al., 2015).
Emerging data reveals that the interaction between psychiatric disorders-including generalized anxiety disorder, panic disorder, major depressive disorder, obbsessive-compulsive and bipolar disorder- and IBS, suggest that this association should not be ignored when developing strategies for screening and treatment (Fadgyas-Stanculete, Buga, Popa-Wagner, & Dumitrascu, 2014).
Conversely, 75 % of patients with major depression and panic disorders have been affected by IBS in lifetime also non concomitantly (Thompson et al., 1999). The prevalence of IBS symptoms in patients with panic disorder varies between 25 to 44% (Gros, Antony, McCabe, & Swinson, 2009; Kaplan, Masand, & Gupta, 1996; Lydiard, 2005) and was of 32% in patients with General Anxiety Disorder (Mayer, Craske, et al., 2001). Several studies have reported a stronger prevalence (27–47,3%) in patients with major depression (onset or recurrent episode) (Masand, Sousou, Gupta, & Kaplan, 1998; Singh et al., 2012).
Case–control studies have shown higher rates of IBS in subjects with other psychiatric disorders compared to controls. These include obsessive compulsive disorder (35.1% in cases vs 2.5% in controls), dysthymia (59.3% in cases vs 1.9% in controls) (Masand et al., 2006), double depression (57.7% cases vs 2.5% in controls) (Masand et al., 1995) and schizophrenia (19.5% vs 2.5%) (Gupta, Masand, Kaplan, Bhandary, & Hendricks, 1997).
As regards IBS, the level of comorbidity far exceeds that seen in other gastrointestinal (GI) disorders (Dinan & Cryan, 2013). This finding support that the dysfunction of bidirectional brain-gut communication contributes to symptom manifestation (Cryan & O'Mahony, 2011; Shanahan & Anton, 1988). The brain influences the function of the enteric nervous system, and the gut influences the brain
via vagal and sympathetic afferents. This link results in neuroendocrine, neuroimmune and other factors interactions. The symptoms may be caused by dysfunctions either primarily in the central nervous system, or in the gut, or by a combination of both (S. E. Kim & Chang, 2012; Mayer & Tillisch, 2011).
5. Pathopysiologic Mechanism
5.1 Stress and Brain-gut axis
“Brain-gut axis” is the term to define the relationship between the gut (enteric nervous system [ENS], luminal wall) and the central nervous system (CNS), including the hypothalamic-pituitary-adrenal axis (HPA). It plays a prominent role in modulation of gut function in health and disease.
The emotional motor system (EMS) in the brain-limbic system and some paralimbic structures, such as the medial prefrontal cortex, amygdala, and hypothalamus, communicate emotional changes via the autonomic nervous system to the gut. The ENS, also called the “brain-in-the-gut,” organizes and coordinates activity of musculature, mucosal epithelium, and vasculature to generate functionally significant patterns of behavior (Mayer, Naliboff, & Chang, 2001; Wood, 2002).
In IBS, stress may act on the emotional limbic system and leads to increased release of adrenocorticotropic hormone and cortisol which act upon the ENS causing the symptoms of IBS such as, abdominal pain, loose stools etc.
The majority of clinical studies support an increased HPA activity at basaline and a higher response under stimulation in patients with IBS without psychiatric comorbidity.
Heitkemper reported increased levels of urinary cortisol compared with healthy subjects, with no difference in patients with and without psychiatric/psychological
disorders (Heitkemper et al., 1996). More recently, Vogelzangs et al. shown that patients with IBS and anxiety disorders present abnormally elevated basal cortisol levels (Vogelzangs, Beekman, de Jonge, & Penninx, 2013).
Conversely, another study suggested that HPA response was attenuated in patients with greater symptom severity and specific psychiatric disorders (e.g., depression, post-traumatic stress disorder, and chronic fatigue syndrome) (Plotsky, Owens, & Nemeroff, 1998). In addiction, other research suggests that individuals with IBS have increased sympathetic nervous system activation (Iovino, Azpiroz, Domingo, & Malagelada, 1995) and alterated cardiovascular autonomic function (Waring, Chui, Japp, Nicol, & Ford, 2004).
Further evidence provided by neuroimaging studies on IBS highligthed that a dysregulation of Central Nervous System (CNS) and ENS could induce dysmotility or visceral sensitivity (H. Mertz et al., 2000; Nakai et al., 2003).
Positron Emission Tomografy (PET) and functional magnetic resonance imaging (fMRI) show patterns of activation and deactivation dysregulated in cortical areas (anterior cingulate cortex, amygdala, insula, prefrontal cortex, thalamus, somatosensory cortex, posterior cingulate, hippocampus and periaqueductal gray) involved in stress response, attention, emotion and pain modulation in patients with IBS compared with controls (H. Mertz et al., 2000; Silverman et al., 1997).
High concordance was reported between the psychological abnormalities in visceral chronic pain disorders and abnormal brain activation patterns in these regions. The perception of pain is modulated by several factors like affective and sensory aspects of the painful stimulus, coping strategies, genetics and personality features (Arntz & Claassens, 2004; Tillisch, Mayer, & Labus, 2011). This has been found especially in the modulatory factors of anxiety, hypervigilance and expectation (Drossman et al., 1999; Posserud, Svedlund, Wallin, & Simren, 2009; D. D. Price et al., 2009). Brain
areas involved in pain modulation were identified as network hubs in IBS (S. M. Berman et al., 2008; Blankstein, Chen, Diamant, & Davis, 2010).
Stress has a crucial role in the pathophysiology of visceral pain as demostrated from experimental stress models, which have been developed to target critical periods throughout the life span, to assess the vulnerability, potential triggers, and the future development of visceral pain. Several preclinical studies show that maternal separation or early-life physical stressors in the form of injury (colonic irritation) can enhance the susceptibility of individuals to develop altered visceral pain responses in adulthood, a key symptom of IBS (Larauche, Mulak, & Tache, 2011). So it seems that altering the dam–pup relationship during sensitive HPA axis phases in the first 2 weeks of life will have long-lasting effects on the stress response and subsequent visceral pain sensitivity.
Furthermore, Wouters and collegues (2012) demostred that stress (such as water avoidance) induced increased pain perception as well as activation of the somatosensory cortex, periacqueductal grey and hippocampus in maternal-separated rats. These findings are in line with studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans (Wouters et al., 2012).
5.2. The immune system
The importance of immune system activation in the development of IBS is well recognized with a bout of inflammatory gastroenteritis conferring increased susceptibility to develop IBS (Spiller & Garsed, 2009). IBS mucosal biopsies display more immune infiltrates such as T-cells, intra-epithelial lymphocytes and mast cells (Chadwick et al., 2002) and soluble mediators secreted from IBS biopsies have excitatory actions on human enteric neurons (Buhner et al., 2009). Involved soluble
mediators, were detected in the plasma of patients with IBS and consist mainly of interleukin 6 and 8 (IL-6, IL-8), CRF, C reactive protein (CRP) and nuclear factor κ-light-chain-enhancer of activated B cells (NFkB). Recently, Bailey et al. (2011) demonstrated that social stress has been reported to increase levels of cytokines, particularly interleukin-6 and monocyte chemotactic protein-1 and the risk of inflammation-related disease, promoting pro-inflammatory gene expression and monocyte differentiation (Bailey et al., 2011). Theese findings, added to that levels of these mediators are also altered in some psychiatric disorders (such as depression and bipolar disorders) higligted the brain-gut link .
The stimulatory effects of the immune and stress factors were additive, with the largest neuronal and contractile response being evoked by the combined presence of all factors (Buckley, O'Halloran, Rae, Dinan, & O'Malley, 2014). These findings are consistent with proposal that hyperactivity of the stress response, in conjunction with low-grade immune activation, may underlie symptom flares in functional bowel disorders (O'Malley, Quigley, Dinan, & Cryan, 2011).
5.3. The Microbiota-brain axis
The most recent literature focuses on the microbiota as a key role in gut-brain communication (“microbiota-brain axis”). The concept that gut microbiota may modulate brain chemistry and behaviour is gaining traction and efforts are now turning to investigate the role of microbiota in animal models of psychopathology (Dinan & Cryan, 2013). At the centre of many of these studies are animals that have been raised in a sterile environment and thus without microbiota, referred to as Germ-Free.
Neufeld and colleagues use female germ-free mice to demonstrate that the absence of a conventional microbiota results in a reduction in anxiety behavior in the elevated plus maze, a well validated model of anxiolytic action. These authors also show an upregulation in the expression of brain derived neurotrophic factor (BDNF) mRNA in the dentate gyrus of the hippocampus of these animals (Neufeld, Kang, Bienenstock, & Foster, 2011). In addition, a down-regulation of the 5-HT1A auto receptor was also present in the dentate gyrus of the germ-free mice (Neufeld et al., 2011). Recently, it has been shown that the gut microbiota is necessary for the expression of the anxiety-like and depressive-like behaviors induced by maternal separation, as indeed prove germ-free mice separated from their mothers in early life that did not show the typical phenotype induced by this early-life stress (De Palma et al., 2015). These data together provide important and direct evidence that microbiota can influence brain and behavior, in this case anxiety.
Conversly, an emerging literature demonstrate that the brain can influence the microbial composition of the gut. These studies have utilized a variety of stressors including pre and post-natal stressors (Bailey & Coe, 1999; Bailey, Lubach, & Coe, 2004; O'Mahony et al., 2009), as well as deprivation of food, water and bedding (Tannock & Savage, 1974), prolonged restraint stress (Bailey et al., 2010), and social disruption (Bailey et al., 2011). These changes may be associated with increased susceptibility to opportunistic infections (Bailey & Coe, 1999), or colonization by pathogenic bacteria (Bailey et al., 2010). Expecially those factors that impact on the normal colonization process during early life, such as psychological stress, may exert long-term effects on the composition of the microbiota that will impact susceptibility to disease.
Finally, some data indicate that patients with psychotic depression may respond to a combination of an antidepressant and minocycline in combination (Miyaoka et al.,
2012). Interestingly minocycline has also been shown to reveres some of the motor and cognitive effects induced by olfactory bulbectomy (Borre, Moloney, Clarke, Dinan, & Cryan, 2014). This adds possibility of the behavioral changes in this model maybe due to alterations in microbial composition. It is intriguing that both IBS symptoms and those of depression respond independently to antibiotics, providing important evidence for the role the microbiota plays in regulating brain function (Dinan, Stanton, & Cryan, 2013).
5.4. Serotoninergic System
Serotonin has a prominent role in the central nervous system (CNS), where it subserves a number of functions including mood and has been implicated in the pathophysiology of anxiety and depression (Hungin et al., 2003), disorders which so commonly coexist with IBS. A recent study shows that 5-HT controlled stress-induced defecation through serotoninergic projection to the ventral hippocampus (Ohmura et al., 2015). On the other hand, the 5-HT has been shown to be involved in the regulation of secretion, motility and perception in the gut (Gershon, 2004; Gershon & Tack, 2007).
Serotonin is synthesized from tryptophan by tryptophan hydroxylase and aromatic amino acid decarboxylase in the enterochromaffin (EC) cells in the intestinal epithelium that produce 90–95% of total 5-HT in the human body (Gershon & Tack, 2007; Matricon et al., 2012). Upon release, 5-HT is inactivated via uptake by the serotonin reuptake transporter (SERT) located among others in the epithelial cells lining the gut lumen (Gershon, 2004; D. Y. Kim & Camilleri, 2000; Mawe, Coates, & Moses, 2006) and broken down by among others the intracellular molecule monoamine oxidase (MAO) into 5-hydroxy indoleacetic acid (5-HIAA), which is excreted in urine (Erspamer & Testini, 1959; Gershon & Tack, 2007; Tack, Janssen,
Wouters, & Boeckxstaens, 2011). Decreased SERT activity results in decreased 5-HT uptake and therefore decreased 5-HIAA production (Nikisch et al., 2004).
Several studies have explored serotonin metabolism in IBS, but results are difficult to interpret and contradicting (Thijssen et al., 2016). It should be acknowledged that data on 5-HT release and activity are influenced by a number of variables: e.g. fasting or (meal) stimulated condition, expression and activity of SERT, reuptake of serotonin within the gut and transport of serotonin in liver, lungs and platelets (Gershon & Tack, 2007) and presence of concurrent psychopathology in IBS patients (Bradford et al., 2012; J. J. Kim, 2008; Sykes, Blanchard, Lackner, Keefer, & Krasner, 2003) such as anxiety and depression (Keszthelyi et al., 2013; Park et al., 2009; Stasi et al., 2013).
There is evidence that patients with IBS have defects in serotonergic signaling. Since then numerous studies have explored the relationship between EC cells, serotonin and IBS. Almost four decades ago, it was discovered that patients with IBS have more number of EC cells as compared to controls (Ahonen, Kyosola, & Penttila, 1976; Kyosola, Penttila, & Salaspuro, 1977).
In addiction, changes in serotonin metabolism have been reported to be more pronounced in patients with psychiatric comorbidity (Abrams & Bishop, 1967; Cremon et al., 2011; J. J. Kim, 2008). A few older studies have assessed the correlation between plasma 5-HT metabolism and anxiety/depression symptoms in IBS patients. Stasi et al. has found a high incidence of specific psychological features including state anxiety (69.69 %), trait anxiety (54.54 %), obsessions and compulsions (28.78 %), in a sample of 105 IBS patients with a correlation between plasma cortisol (marker of HPA axis activaction) and serotonin in diarrhea-predominant IBS (Stasi et al., 2013). But theese results were not in line with each other and do not point to a specific direction of influence by anxiety or depression
disorders on 5-HT metabolism (Park et al., 2009; Stasi et al., 2013). Keszthelyi et al., instead, noted a significant correlation between mucosal concentrations of 5-HT and psychological state in IBS patients (Keszthelyi et al., 2013).
This is an important assumption since IBS patients have been shown to be hypervigilant regarding gastrointestinal symptoms (Posserud et al., 2009). Potential alterations in gastrointestinal homeostasis may therefore be augmented by hypervigilance and contribute to increased disease burden.
In the search for an explanation to these controversial data, genetic polymorphism in Serotoninergic System has been extensively investigated.
5.4 a. SERT Poymorphism in IBS
Some studies have focused on genomics and on the polymorphic region (5-HT transporter long polymorphic repeat – 5-HTTLPR) of the gene that encodes the serotonin transporter (SERT). Despite initial promise, associations between 5-HTTLPR polymorphisms and IBS have been found to have a limited role (Zhang et al., 2014), but may be predictive of serotonergic drug responses (Acosta & Camilleri, 2015).
The SERT gene, also known as solute carrier family 6 member 4 (SLC6A4), was mapped to chromosome 17q11.2 by Ramamoorthy et al. in 1993. Polymorphic loci that affect the expression and function of SERT gene have been identified (Ramamoorthy et al., 1993). There is a GC base pair rich repetitive sequence located at 5’ regulatory end of the SERT gene and is labeled as 5-HT transporter linked promoter region (5-HTT LPR). Polymorphism due to deletion or insertion of 44 base pairs in this region resulting in a long (L) and short (S) allele was first discovered by Heils et al (Heils et al., 1996). Individuals containing the l variant tended to have higher transcription and expression activity than those with the s variant, indicating
that the L/L genotype promoter could be more powerful than the S/S genotype promoter (Y. M. Wang et al., 2012). The homozygosis for the short variant (S/S) and heterozygous (L/S) are associated and a reduction in transcription of the SERT gene and the encoded protein has a lower efficiency in the process of 5-HT reuptake compared to homozygosis for the long variant (L/L) (Chen, Pan, Rothman, Wade, & Gershon, 1998).
Decreased mucosal SERT activity in IBS may result in an increase in mucosal availability of 5-HT leading to luminal hypersensitivity, hypermotility and diarrhoea. It has been speculated that continuous exposure of the mucosa to 5-HT may eventually result in the desensitization of 5-HT receptors with decreased reflex activity and give rise to luminal hyposecretion and constipation (Coates et al., 2004; Shekhar et al., 2013).
One of larger studies has demonstrated no differences between SLC6A4 genotype in IBS patients and healthy controls (H. J. Kim et al., 2004).
The evidence on the relationship between different genotypes and their phenotypic expression comes from a study conducted by Lesch et al (Lesch et al., 1996), which found that S/S genotype had less HT uptake resulting in higher blood levels of 5-HT as compared to other L/L and S/L genotypes (Lesch et al., 1996). Wang et al. showed that the homozygous genotype (L/L) can increase the expression of SERT in the colonic mucosa (Y. M. Wang et al., 2012). Further, in patients with S/S genotype Fukudo et al. reported a greater activation of the cortical areas, normally triggered by emotional stimuli, in response to colorectal distention (Fukudo et al., 2009). Kim et al highlighted an association between S/S genotype IBS patients, in combination with the variant allele polymorphism of the adrenergic receptor α2c characterized by the deletion of the nucleotide sequence 322-325 [α2c-DEL (322 -325)], and greater severity of extraintestinal symptoms like headaches, back pain, sleep disturbances
and fatigue, as well as an increased incidence of psychiatric comorbidity, compared to healty controls. This suggests that the 5-HTTLPR polymorphism is involved in the stress response of patients with IBS (H. J. Kim et al., 2004).
Several researchers have explored the association between IBS subgroups and SERT gene since then but have come up with conflicting results (Atkinson et al., 2006; Dai, Zheng, & Jiang, 2013; Pata et al., 2002; Sikander et al., 2009), due in part to the ethnic difference (Areeshi, Haque, Panda, & Mandal, 2013; Choi et al., 2014; Zhang et al., 2014).
5.4 b. SERT in psychiatric disorders
Such as the catecholamine system of the brain is likely associated with the temperament profile, so the genetics of the serotonin (and norepinephrine) systems could influence the depression-associated behavioral traits.
Indeed, a less efficient serotonin pathway due functional polymorphism (5-HTTLPR) within SERT, has been related to personality dimensions such as neuroticism, emotional reactivity to negative events, to a temperamental level towards less adaptive behavior and to increased risk of affective disorders (Cloninger, Svrakic, & Przybeck, 1993; Xie, Kranzler, Farrer, & Gelernter, 2012). Therefore, the S-allele has in some studies been referred to as the “weak allele“, associated with several mood and anxiety disorders (Herrmann et al., 2015), and has been identified with poorer antidepressant treatment response (Cloninger, Zohar, Hirschmann, & Dahan, 2012; Gonda et al., 2009; Lesch et al., 1996; Serretti, Kato, De Ronchi, & Kinoshita, 2007).
In a recent study in patients with Major Depressive Disorder (MDD) according to DSMIV and Montgomery-Asberg depression rating scale (score of at least 20), Andre K. Et al. finding that patients with SS-genotype of 5-HTTLPR having higher
“Persistence” scores (P) at Temperament and Character Inventory (TCI) and this could possibly be explained by less efficient serotonin signaling caused by short S-allele (Andre et al., 2015). According to Cloninger’s psychobiological personality model, P reflects the tendency to persevere despite frustration and fatigue, may predispose to compulsiveness and could be viewed as a negative trait in recovering from stressful or traumatic experiences (Cloninger et al., 1993; Montgomery & Asberg, 1979).
The S-allele may predispose to post-traumatic stress disorder (PTSD) after an exposure to traumatic experiences (Lee et al., 2005; Z. Wang et al., 2011; Xie et al., 2009), although some contradictory findings exist (Grabe et al., 2009; Thakur, Joober, & Brunet, 2009), and also to poorer response to antidepressant treatment in PTSD (Lee et al., 2005; Mushtaq, Ali, Margoob, Murtaza, & Andrade, 2012; Z. Wang et al., 2011).
The S-allele of 5-HTTLPR has also been associated with poorer memory function, although these results are not entirely consistent (Mannie, Barnes, Bristow, Harmer, & Cowen, 2009; J. S. Price et al., 2013; Zilles et al., 2012). Poorer memory function could potentially explain why recovering from PTSD and some other psychiatric disorders may be inefficient because of impaired adaptive skills to learn new coping mechanisms.
In contrast with most of the literature, in a recent review, Homberg and Lesch argued that the short variant of the 5-HTTLPR must also carry beneficial effects, since it is unlikely that disease-associated polymorphisms are maintained throughout evolution if they only lead to negative consequences (Homberg & Lesch, 2011). To underscore the value of this argument, they summarized a large number of studies showing positive effects of the short (S) allele on cognitive functions. Based on these studies, they postulated a potential model for the interaction between increased cognitive
functions and increased negative emotionality in S-allele carriers: individuals with the S-allele show an enhanced sensitivity to salient information in their environment (hypervigilance), which in turn leads to increased sensitivity to negative events, but also to beneficial effects on social cognition. This assumption is supported by a recent study, which showed that human mothers carrying the S-allele were more sensitive toward their children (Cents et al., 2014)
Also, several neuroimmaging study have been performed. In a recent SPECT study (Lin et al., 2015), aimed to investigate whether there is an interaction effect between environmental stress and availability of thalamic and amygdala SERT levels, as a gene-by-environment interaction effect, was found that only the SERT availability in the thalamus moderated the association between environmental stress and depressive tendency among males. The study shows that those with lower levels of SERT availability may be more vulnerable to depressive symptoms induced by perceived stress. This finding provides new evidence that confirms the role of the serotonergic system in the association between stress and depression (Lin et al., 2015).
The association between 5-HTTLPR genotype and antidepressant treatment response has also been widely studied with conflicting results. There are several reports that patients with unipolar depression carrying the L-genotype show better response to or are more likely to achieve remission with antidepressants than carriers of the S-allele of 5-HTTLPR (Illi et al., 2011; Serretti, Benedetti, Zanardi, & Smeraldi, 2005; Smeraldi et al., 1998). Conversely the S-allele has been suggested to predict better treatment outcome in some studies with Asian unipolar depression patients (D. K. Kim et al., 2000; H. Kim et al., 2006; Yoshida et al., 2002). No evidence to support the 5-HTTLPR polymorphism as a predictive tool for antidepressive treatment responsiveness in patients with MDD was found by Lewis et al. (Lewis et al., 2011). Moreover, a large meta-analysis by Taylor et al. (Taylor, Sen, & Bhagwagar, 2010)
detected no associations between 5-HTTLPR genotype and antidepressive treatment response.
6. Therapeutic strategy in IBS
Although some patients may improve solely after reassurance that they have a functional disorder, the diagnosis of IBS often leads to a variety of medication trials, intermittent usage of antispasmodics, therapy for constipation and/or diarrhea, and agents for associated neuropathic pain. Based on the brain-gut axis and hypothesis of signaling or metabolism regarding serotonin perturbations, has been suggested that antidepressant medications such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be effective in treating the symptoms of IBS (Garvin & Wiley, 2008). The mechanism of action of these agents remains unclear. It may be related to one or more multiple effects in both central (on mood, anxiety and algesia) and peripheral (on GI motility or on receptors for neuropathic pain) level (Gorard, Libby, & Farthing, 1994, 1995; Onghena & Van Houdenhove, 1992; Su & Gebhart, 1998). It is also unclear if efficacy in IBS is due to their effect on the 5-HT or on the cholinergic system.
To date, the evidence for benefit of antidepressant treatment in patients with IBS and comorbid depression was limited and contradictory. Some antidepressants may help symptoms of IBS, although remains to be elucidated if the same drugs and dosages have been associated with improvements in concomitant depressive symptoms (Friedrich, Grady, & Wall, 2010).
Tricyclic antidepressants (TCAs) are frequently used to treat IBS, especially those with more severe and refractory symptoms (H. R. Mertz, 2003). Several randomised, placebo-controlled trials have supported the use of low-dose TCAs in the treatment
of IBS patients (Gilkin, 2005; Quartero, Meineche-Schmidt, Muris, Rubin, & de Wit, 2005; Wald, 2002).
In a meta-analysis, Jackson et al. failed to observe a beneficial effect of TCA on global IBS symptoms or abdominal pain, mainly due to insufficient statistical power, although they were effective against depressive and anxiety symptoms (Jackson et al., 2000). Conversely, in more recently meta-analisys Ford at al. (Ford, Talley, Schoenfeld, Quigley, & Moayyedi, 2009) found that 3 studies did not demonstrate a significant relationship between depression scores and improvement in IBS symptoms (Tabas et al., 2004; Tack et al., 2006; Vij, 1991); 1 trial reported higher symptom response in patients without concomitant depression (Drossman et al., 2003).
Because of side effects of TCAs, SSRIs may be useful in IBS. Several case reports suggested that SSRIs such as paroxetine and fluvoxamine may alleviate IBS symptoms (Emmanuel, Lydiard, & Crawford, 1997; Kato & Misawa, 2005; Kirsch & Louie, 2000). SSRIs can alter bowel physiology; for example, paroxetine can accelerate smallbowel transit without affecting gastric emptying or colonic transit (Chial et al., 2003), provide some benefit in chronic pain syndromes (Patkar et al., 2007) such as migraine (Moja, Cusi, Sterzi, & Canepari, 2005), fibromyalgia (Pae et al., 2009), neuropathic pain (Saarto & Wiffen, 2005) and back pain. Moreover, paroxetine has proven efficacy for major depressive disorder and anxiety disorders, which are common in patients with IBS (Masand et al., 2009). Probably, the effects of SSRIs on widespread somatic symptoms are more important than those on the gut. SSRIs have shown to be effective in a variety of somatoform disorders (Clouse & Lustman, 2005) and alleviate global distress (Masand et al., 2006). Finally it has been suggested that SSRIs may induce an affective memory bias towards positive material without significantly influencing the mood status (Kilkens, Honig, Fekkes,
& Brummer, 2005). This could reduce attention to unpleasant gastrointestinal sensations and modify unrealistic anxieties of patients that symptoms imply serious illness (Creed, 2006).
Paroxetine has been the most widely studied SSRI in placebo-controlled trials. In the first such study (Tabas et al., 2004), in patients with or without comorbid anxiety and depressive disorders, was found that paroxetine (10–40 mg/day) was significantly superior to placebo on the improvement in sense of well-being (over the 12-week study period). Moreover, the proportion of subjects experiencing an improvement in bowel movements such as straining, urgency and feeling of incomplete evacuation was significantly higher in the paroxetine group (58.6%) than in the placebo group (32.4%). Interestingly, at the end of the study, prior to unblinding, significantly more paroxetine recipients (84%) than placebo recipients (37%) desired to continue their study medication, indicating a favourable effect of paroxetine for IBS patients compared to placebo.
In a open-labelstudy by Masand, the effectiveness of the selective serotonin reuptake inhibitor paroxetine was comparable in IBS patients with and without a coexisting anxiety disorder (Masand et al., 2002).
Although paroxetine was somewhat more effective in alleviating abdominal pain, pain frequency, and pain severity in patients with anxiety disorder than in those without anxiety disorder, the differences were not statistically significant (Marks et al., 2008). In contrast, Masand et al. also reported that, in IBS patients according to Rome III Criteria, and without current mood or anxiety disorders (but with subsyndromal mood or anxiety symptoms or a past history of mood or anxiety disorders), paroxetine may provide global benefit even though it did not improve symptoms of abdominal pain (Masand et al., 2009).
Citalopram was found to be beneficial and well-tolerated in patients with IBS (Masand et al., 2005). Also, a 6-week crossover trial of citalopram in non-depressed IBS patients (3 weeks: 20 mg/day; 6 weeks: 40 mg/day), showed a significantly improvment of abdominal pain, bloating, impact of symptoms on daily life, and overall well-being, as compared with placebo (Tack et al., 2006). Changes in depression or anxiety scores were not related to IBS symptom improvement.
Conversly, in a more recent study, Ladabaum et al. found citalopram was not superior to placebo in treating non-depressed patients with IBS, and changes in clinical symptoms were not substantially correlated with changes in rectal sensation (Ladabaum et al., 2010). Furthermore Thijssen et al., shown that acute administration of citalopram in IBS patients resulted in increased PPP 5-HT levels in combination with enhanced memory performance, leading to the assumption that SSRI administration increases 5-HT at synapses, but it is still uncertain how this may affect 5-HT activity at CNS or intestinal level (Thijssen et al., 2016).
Fluoxetine was also studied in patients with IBS, demonstrating a nonsignificant therapeutic difference on global symptom relief without improvement in abdominal pain severity, compared to controls. Possible explanations include inadequate power to detect the difference (40 subjects) and possible under-dosing of fluoxetine (20 mg/die) (Kuiken, Tytgat, & Boeckxstaens, 2003). Another randomised double-bind study showed that fluoxetine was superior to placebo in improving symptoms of pain, bloating, and constipation in 44 pain and constipation-predominant IBS patients (Vahedi, Merat, Rashidioon, Ghoddoosi, & Malekzadeh, 2005).
7. Aim of the study
The aim of this study was to assess:
1) Specific psychopatological features in IBS patients and possible correlation with GI symptoms severity and quality of life.
2) Efficacy and safety of psychopharmacological treatment with SSRI medication on GI symptoms through a study period of sixteen weeks.
3) Correlation between SERT polymorphism and clinical parameters and drug response.
8. Study design
This is a observational open-label study. A total of 150 consecutive patients (35 M-115 F; age range 19-79; mean age 40.95±13.9) affected with IBS according to Rome III criteria (Longstreth et al., 2006), who were referred to the Gastroenterology Unit of the University of Pisa from 2012 to 2015 were evaluated for enrollment.
Patients admitted to the study assumed Paroxetine once a day. Based on tolerability and response, Paroxetine was started at 5 mg/day increased every five days in 5 mg increments, the maximum dose being 20 mg. Higher dosage could have been authorised in the judjment of clinician. No other psychotropic medications were permitted except for medications to alleviate treatment.
Patients were evaluated at regular intervals (at 2nd, 4th, 8th, 12th and 16th weeks). At the end of the 16th weeks, the medication was tapered over 2 weeks or more if necessary (maximum two months).
Follow-up surveillance was done during tapering and after 24th to end of the study (56th week) at regular intervals.
The analysis also had a comparison between SERT polymorphism and the study parameters, but since only 91 patients provided the saliva sample for genetic
screening, these data appears to be incomplete and not reiliable for statistical analysis.
Inclusion criteria: -Age range 18-80 years
-Patients able to comly with thw study procedures. Exclusion criteria:
-Patients with severe concurrent medical disease or previous major abdominal surgery, presence of significant alterations to routine blood tests, the presence of organic changes endoscopic examination of the colon.
-Patients who had psychiatric comorbidities for which Paroxetine was controindicated.
-Patients who had severe psychiatic disorder. - Pregnancy or lactation.
Written informed consent was obtained from all subjects before we performed any study procedures. The study was approved by the local Ethics Committee.
9. Instruments
9.1. Gastrointestinal assessment
A specific questionnaire, IBS Symptome Severity Score (IBS-SSS), assess severity of gastrointestinal symptomps.
It consisted of questions (15 items) pertaining to diagnosis of IBS and its subtypes using Rome III criteria (Longstreth et al., 2006). The severity of the IBS symptoms (IBS severity) was assessed using irritable bowel severity scoring system based on severity of pain perceived, number of pain days, days and severity of abdominal distension, satsfaction with bowel habit and the quantization of interference in the patient’s general life by these symptoms. Each of these questions generated a
maximum score of 100 using prompted visual analogue scales. Scores generated for each of these modalities were summed up to get the final severity score (maximum up to 500). On the basis of the cumulative severity score, patients were classified having mild IBS (IBS severity score 75-175), moderately severe IBS (score175-300) and severe IBS (score > 300) (Francis, Morris, & Whorwell, 1997).
It was administered at baseline, 4th and 16th week.
9.2. Psychometrics and quality of life assessment
Structured Clinical Interview for DSM-IV Patient Edition (SCID IV) (First M.B., 1997)
Is a Structured Clinical Interview used to determine Axis I disorders (major mental disorders) according to DSM-IV categorical criteria (Spitzer, Williams, Gibbon, & First, 1992). The instrument was designed to be administered by a clinician or trained mental health professional.
It consists in of a first part that aimed aims to elicit demographic data, such as work and educational level, medical and pharmacological history. The second part is organized into different sections: Mood Disorders, episodes (section A), Psychotic symptoms associated to mood disorders (section B), Psychotic Disorders (section C), Mood Disorders, course (section D), Substance Abuse Disorders (section E), Anxiety Disorders (section F), Somatoform Disorders (section G), Eating Disorders (section H), Adjustment Disorders (section I).
Clinical Global Impressions (CGI)
Provides an overall assessment of psychopathological features.
This scale were specially formulated by the Psychopharmacology Research Branch (PRB) of the National Institute of Mental Health as part of an extensive research on schizophrenia, becoming the most widely used in clinical psychopharmacology. Consist in 3 areas: severity of disease, global improvement and index of therapeutic efficacy. The psychiatrist gives a score from 1 (normal, no disease) to 7 (severely ill) at each evaluation, including baseline. Area of improvement must be completed only after the first one assessment, the measure of effectiveness expresses only if we have to evaluate the relationship between efficacy and side effects.
Each item is priced separately. There isn't a total score . It was administered at baseline, 4th and 16th week.
Hamilton Rating Scale for Anxiety (HRSA or HAM-A) (Hamilton, 1959)
Is the most used in the study of anxiety and of its modifications under treatment while not being able to distinguish different specific anxiety disorders. This scale explores in 14 items several symptoms such as anxiety, tension, autonomic symptoms, somatic symptoms and behavior during the interview. Each symptomatologic category is evaluated by a score from 0 (absent) to 4 (severe) with a possible total score between 0 and 56. A score ≤17 indicates a mild disorder, 18-24 a moderate disorder, 25-30 a severe disorder (Hamilton, 1959). The interview refers to symptoms experienced by patient in the previous week and finally completed with observation of the behavior during interview.
Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979)
Measures the severity of depressive symptoms using 10 item. Each item has a score according to the severity and frequency of symptoms (0: absence of the symptom - 6: Maximum severity). The rating currency also, to some extent, duration and functional impairment (tension, sleep disturbance, energy, appetite, concentration). A score between 0 and 6 indicates absence of depression; between 7-19 mild depression; between 20-34 moderate depression; ≥ 35 severe depression (Snaith, Harrop, Newby, & Teale, 1986).
It was administered at baseline, 4th and 16th week.
Symptom Check List (SCL-90)
Is a relatively brief self-report psychometric instrument published by the Clinical Assessment division of the Pearson Assessment & Information group. It is designed to evaluate a broad range of psychopathological symptoms. It is also used in measuring the progress and outcome of psychiatric and psychological treatments or for research purposes. It consist in 90 items on disturbances which patient may have experienced in the last week. The subject provides an assessment from 0 (not at all) to 4 (very much) for each item. The results identify ten symptomatologic dimensions: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism and sleep disorders. For each of them the relative score is calculated as the average of the questions answered. In general it is considered interesting the average scores equal or higher than 1. It 'also possible to calculate a global index (GSI Global Score Index) as the average score of all the answers to the test.
Quality of Life Enjoyment and Satisfaction Questionnaire (QLES-Q)
It’s a self-assessment questionnaire that explores the degree of satisfaction experienced by the subject in several areas of daily functioning in the last week (Endicott, Nee, Harrison, & Blumenthal, 1993). It consists of 93 items grouped into 8 domains: health / physical activity (13 items), subjective feelings (14 items), work (13 items), household chores (10 items), school/course work (10 items), the leisure activities (6 items), social relationships (11 items) and general activities (16 items). Each item is rated from 1 to 5 points, and higher scores express greater satisfaction and greater pleasure.
It was administered at baseline and 16th week.
Arizona Sexual Experience Scale (ASEX)
This questionnaire consists of 5 items that assess sexual function by examining sexual desire, arousal, erection / vaginal lubrification, ability to reach orgasm, orgasm and satisfaction. Each item provides a rating from 1 (hyperfunction) to 6 (hypofunction) and a total score ranging from 5 to 30. A score> 18 indicated a clinically significant sexual dysfunction (McGahuey et al., 2000).
It was administered at baselineand 16th week.
9.3. Genetic analysis polymorfism 5HTTLPR
A sample of saliva from the patients was collected by swab for the subsequent extraction of genomic DNA on which to perform genotyping of region 5-HTTLPR. The DNA extraction was performed using specific primers, which identify the promoter region of the gene 5HTTLPR, used for PCR amplification.
The saliva samples were stored at -20 ° until of the genotype evaluation. Genomic DNA was isolated by use of a QIAamp DNA Mini Kit Kit (Qiagen) and quantified by spectrophotometry.
Specific primers were designed (primers) for amplifying genomic DNA regions containing the short (S variants) and long (L) 5-HTTLPR. The primers designed for this purpose are the following:
LPR-F: 5'-GGCGTTGCCGCTCTGAATGC-3 'sense, corresponding to the nucleotide sequence ranging from -1416 to -1397 the 5' end of the promoter region of the SERT gene;
- LPR-R: 5'-GAGGGACTGAGCTGGACAACCAC-3 'antisense, corresponding to nucleotide sequence that ranges from -910 to -888 at the 5' of the promoter region of the SERT gene.
The PCR reaction was performed in a final volume of 50 l containing the following reagents: 1 ml of genomic DNA, 25 l of water DNAase free, 1 ml of dNTPs, 1µl of LPR-F primer, primer LPR 1ml -R, 10 l of BUFFER GC resolution, 10 l of 5x BUFFER DMSO and 1 ml of AmpliTaq polymerase enzyme (Roche Diagnostics). The reaction was conducted in a PCR Express thermic cycler (HYBAID) on the basis of the following amplification protocol:
• Initial denaturation of genomic DNA at 94 ° C for 3 minutes; • Denaturation at 94 ° for 1 minute;
• Annealing at 55 ° C for 1 minute; 35 cycles • Extension at 72 ° C for 1 minute;
• Final extension at 72 ° C for 7 minutes.
The amplification products were visualized by electrophoretic separation of DNA in 2% agarose gel in 1X TAE buffer (10X TAE: 48.4 g of Tris base in 800 ml of distilled water, 11:42 ml of glacial acetic acid, 20 ml of EDTA 0.5 M brought to a
final volume of 1 liter with distilled water, autoclaved) containing 3.5 L of ethidium bromide (10 mg / ml). The bands relative to the PCR products are accessed using a transilluminator UV LIGHT Ultraviolet (BioRad Richmond, CA, USA) and photographed with a Polaroid device MP4 Land Camera (Polaroid, MA, USA).
10. Statystical Analysis
Descriptive statistics provided computation of means and standard deviations. Mann-Whitney and Kruskal-Wallis tests were utilized to compare two and three groups respectively as all the variables treated are not normally distributed. Similarly, in the longitudinal analyses, Wilcoxon and Friedman tests were used.
To assess longitudinal group differences an useful index representing the proportion of improvement respect the maximum possible was defined for each considered variable (V):
IDX(V)=(VT0-VT16)/VT0
where VT0 is the variable’s value at baseline and VT16 is the variable’s value at the
final time of observation.
Different the calculation for QLESQ total score having a decreasing values of severity:
11. Results
11.1. Descriptive and Baseline Analysis
Demographic features are shown in table n 1. The mean age was 40.95±13.9 and there was a female prevalence (76.6% vs 23.3%). Most of patients had more than eight years of schooling (48,6%), were married (46%) and was employeed (80,6%). In table 2 shows the prevalence according to the type of bowel function: IBS-D (47,3%), IBS-C (32%), IBS-A (20,7%). The L/S polymorphism of 5HTTLPR gene has a frequency of 34% comparad with L/L (19,33%) and S/S (7,3%) as shown in table 3.
Data relating to psychopathological aspects (Axis I diagnosis, family history of psychiatric disorders, psychopharmacological or psychological treatment) are shown in tables 4 and figure 1. The 58% had negative family history to psychiatric disorders compared with 42% that at least one first-degree relative affected (table 4 a).
The 69.3% had no Axis I diagnosis, while 30.6% of patients had one or several Axis I lifetime diagnosis, mainly Panic Disorder (PAD=17,4%), Major Depressive Episode (MDE=14,7%), Nervous Anorexia (NA=3,3%) and General Anxiety Disorder (GAD=2,7%) (Figure 1). Most of the patients had never taken medication (56% vs 44%) and the 30,3% are taking a targeted treatment at baseline. Benzodiazepines were the most used in this sample in lifetime (33,3%) and at baseline (9,3%). A 14% of patients made a psychotherapy lifetime (Table 4b). The mean scores for evaluations scales are shown in the Table 5. The SLC-90 and QLES-Q domains were also weighed and percentualizzate to make them comparable (Figure 2 and 3).
The sample of 150 patients have a moderatly severe GI symptomatology (IBS-SSS scale 285,1±98,6) (Table 5 a). Regarding the psychopathological features, these patients are defined by mild symptoms of anxiety and depression (HAMA
14,89±8,24 and MADRS 8,95±7,84) and seem to be only marginally-mildly impaired according psychic clinical judgement (CGI 2,77±1,14) (Table 5 b). These data are in agreement with self-assessment evaluation (SCL-90 65±49,2) (Table 5 c), which also shows a higher scores in the obsessivity (24,48%), depression (23,33%), somatization (22,95%) and anxiety (19,68%) domains (Figure 2). The quality of life is however relatively satisfactory (QLESQ 194,54±35,42) (Table 5 d), although it appears a lower satisfaction in leisure (58,82%) and physical state (59,39%) areas (Figure 3). The sexual behavior of these patients are not impaired at baseline (ASEX 15,6±4,68) (Table 5 b).
A) Splitting the sample according to the presence or not of “psychopathological features” (IBS/Psy) that include those with a history of Axis I diagnosis (30,6%), regardless of treatment, and those who have never had any diagnosis of axis I but have a history of treatment (25,3%), indicating a lifetime psychological distress, as shown in Table 6 a. IBS/Psy represents slightly more than half (56%) of the total sample (Table 6 b).
These patients are defined by scores in all scales exploring gastrointestinal and mental well-being higher than “With not psychoapathological features” group (IBS/NoPsy), as shown in Table 7 a, b, c, and a worse quality of life in all areas (Table 7 d). As regards the psychopathological self assessment and quality of life, Figure 4 and 5 shown the domains scores for IBS/Psy and IBS/NoPsy.
By comparison between the two groups we found significative differences in GI symptoms and frequence of abdominal pain (Table 8 a), in almost all psychopathological self and by-investigator assessed, with more severe in IBS/Psy group (Table 8 b and c). IBS/Psy results also significantly impeired in physical state,
subjective feeling of well-being and in leisure activities compared to IBS/NoPsy (Table 8 d).
B) Within the IBS/Psy we divided the patients with severe (IBS-SSS>300) and patients with mild to moderate GI symptoms (IBS-SSS≤300), thus obtaining two subgoups both the 50% of IBS/Psy subjects (Table 9 a) defined as in table 9 b, c and d and figure 6 and 7.
By comparison we found significative differences in anxiety and depression assessed by-investigator and in satisfaction of own physical state with more severe in IBS/Psy&IBS-SSS>300 group (Table 9 e).
C) Doing the same division in IBS/NoPsy group, we find a subgroup with severe IBS (IBS/NoPsy&IBS-SSS>300) and another with mild to moderete GI symptoms (IBS/NoPsy&IBS-SSS≤300), respectively the 36,3% and 63,7% of IBS/NoPsy patients (Table 10 a). These subtypes are characterized as in Table 10 b, c, d and figure 8 and 9.
Comparing IBS/NoPsy&IBS-SSS>300 and IBS/NoPsy&IBS-SSS≤300 patients, we found significative differences in all assessed by-investigator psychopathological scale and according to psychic judjement with more severe in IBS/NoPsy&IBS-SSS>300 group (Table 10 e). This subgroups results also significantly severe in OC symptomatology in self-assement evaluation in (Table 10 f) compared to the others patients.
A1) Taking into account the “GI features”, we divided the sample according to severity of GI Symptoms and we get two populations, respectively with severe GI symptoms (IBS-SSS>300) and with mild to moderate GI symptoms (IBS-SSS≤300).
IBS>300 represents the 44,7 % and the IBS-SSS≤300 the 55,3% of total sample (Table 11 a). The IBS-SSS>300 group provides the higer scores in all psychopatological by-investigator and self assessment as well as according to psychic clinical judgement (Table 11 b and 11 d, Figure 10), and lower scores in the satisfaction evaluation (table 11 d and figure 11), wich have a decreasing values of severity. Statistically significant difference have been found in depression and anxiety assessed by-investigator and in the psychic clinical judgement (Table 11 e) with more severely for IBS-SSS>300 group. This patients shown also statistically significant severity in SCL-90 OC and SOM domains (Table 11 f) as well as in PS area and quality of life totally (Table 11 g).
B1) Within the IBS-SSS>300 group we shared the IBS/Psy and IBS/NoPsy patients, thus obtaining two subgoups respectively of 67,2% and 37,3% of the IBS-SSS>300 subjects (Table 12 a) defined as in table 12 b, c, d, and figure 12 and 13.
By comparison between the two subgroups we found significative differences in all by-investigator and almost all self-assessed psychopathological scale with more severe in IBS-SSS>300&IBS/Psy group (Table 12 e, f). This subgroups results also significantly impaired in physical state, leisure and global satisfaction compared to the other (Table 12 g).
C1) Then, we did the same division in IBS-SSS≤300 to characterize the IBS/Psy and NoPsy with mild to moderate GI symptoms, respectevely 50,6% and 49,4% of the IBS≤300 (Table 13 a, b, c, d and Figure 14, 15). Comparing these subgroups we found significative differences in all by-investigator and self-assessed psychopathological scale with more severe in IBS-SSS<300&IBS/Psy group (Table
13 e, f). This subgroups results also significantly unsatisfied in physical state (Table 13 g) compared to IBS<300&IBS/NoPsy.
D) We finally considered a group characterized by presence of “psychopathological features” not severe GI symptoms (IBS-SSS≤300) and called it “IBS/Brain” (28%). Converesely, we put in another group the patients “whith not psychopathological features” but that have a severe GI symptoms (“IBS/Gut”-16%). The scores of two groups shown in Table 14 b, c, d and Figure 16, 17.
From comparison between these group we found that the IBS/Brain appears statistically more severe in all psychopathological assessment (self, by-investigator and according to psychic judgement). Furthermore thes patients self-evaluated significantly severe in somatization, sensation subjective and paranoid ideation compared to IBS/Gut sample (Table 14 e, f). No differens in terms of quality of life were found.
11.2. Longitudinal Analysis
Twenty patients among the 150 didn’t give the consent to the study because they felt to be relative GI wellbeing at the moment of interview.
Twenty patients were excluded from the study for the presence of psychiatric disorders requesting tratment different to study medication or for pregnancy or lactation (female patients).
Although oriented to verbal consent, sixty patients failed to go on into the study procedure for different reasons: problems in submitting to frequent medical examination (distance, work etc.), stigma versus psychopharmacologic treatment (fear to be considered “crazy”), side effects of medication. Some of these patients
delayed the consent untill they have consulted their general practioner (GP), but in few cases GP were not agree with this terapeuthical approach.
Totally, fifty patients entered in the study. A part of these (N=16) dropped out respectively at the 2nd, 4th, 8th or 12th week of treatment, because of a) side effects related to treatment (weight gain, sexual disorders, sedation, asthenia), b) sensations of worsening in GI symptomatology c) other emergent symptoms different from baseline (menorrhagia, onset of neurological symptoms), d) worsening of psychiatric condiction requesting more intensive treatment, e) planning to become pregnant. Thirty-four patients carried on study procedure during all the active phase of treatment (16th week).
Comparing these patients (N = 34) through the time (baseline, 4th and 16th week) we find a significant improvement in GI and psychopathological symptoms as early as the 4th week (Table 15 a, b). The improvement is preserved until the 16th week (Table 16 a, b), except for CGI1, CGI3 (Table 17 a and b), and SCL-90 in total score and in Anxiety domain (Table 17 c) which show a further improvement to the 16th week. Despite a significant worsening in term of sexual symptoms (Table 17 d), the medication is well tolerated as evidenced by the significant improvement of Efficacy/Adverse size (Table 17 b).
The quality of life and satisfaction also significantly improved after 16 weeks (Table 17 e) and the QLESQ almost reached the 72% of full possible improvement (Figure 3).
In order to compare the time trend between different groups of patients we formulated an index of improvement called IDX (see “Statistical Analysis).
Considering the alvo subgroups (IBS-A,D, C), it shows that the improvement of self-assessed psychopathological anxiety and sensitivity symptoms is affected by the type
of bowel function as indicated by the statistically significant higher scores in Anxiety domain in IBS-D patients compared to the others and in Sensitivity domain compaired with only the IBS-C patients (Table 18).
On the other hand, the improvement does not seems affected by SERT polymorphisms.
Instead, psychopathological features (in IBS/Psy group) did not influence the GI symptoms improvement, nor of those self and by investigator psychopathological assessment or general quality of life. As it emerges a significantly greater improvement for IBS/Psy group in the leisure domain of QLESQ (Table 19), compared to IBS/NoPsy goup.
Despite the fact that IBS/Psy being worse than IBS/NoPsy group, these improve at the same way.
The gastrointestinal symptoms severity seems to be influence the somatization and phobia domains of self assessment in psychopathological evaluations, with a significantly major improvement in the patients with mild to moderate GI symptoms (Table 20).
The GI severity did not influence the improvement either in the IBS/Psy or IBS/NoPsy group.
The Psychopathological features did not influence the improvement either in in the IBS-SSS>300 or IBS-SSS≤300 group.
Between IBS/Brain and IBS/Gut not found significantly differences in terms of improvement.
12. Discussion
The relationship between IBS and psychiatric disorder had been subject of interest of several authors and there are extensive data in literature. However, data are often conflicting and there is no agreement among the various authors on this topic. Reasons for this, apart from the complexity of the matter, are due to methodological differences involved in study procedure of the resarches.
Our study fully reflects the disputes concerning the intriguing question “irritable brain or irritable bowel”. The results run counter to a confirmation of a high psychiatric comorbidity in IBS - most notably mood and anxiety disorders - in the sense of full diagnosis (one third of the sample met criteria for Axis I mental disorder) or also of other psychopathological implications.
According to literaure PD, MDE and GAD were the most represented diagnosis in this sample, suggesting that this comorbid conditions may influence the course and the outcome of IBS.
A particular value of this study is the use of a structured clinical interview for mental disorder to make more reliable the psychiatric diagnosis, differently from a large part of papers that take into consideration only psychiatric ratings for diagnostic judgement. Moreover, independently from full-blown diagnosis, clinical observation of IBS patients highlighted some “vulnerability psychological features” often noted by the gastroenterologist themselves. For this purpose we included in the IBS/Psy group not only subjects with psychiatric diagnosis but also with other features such as lifetime psychopharmacological (or psychoterapeutics) treatment, probably indicating an underlying soft psychiatric distress. It is likely that IBS/Psy lacking Axis I diagnosis, could have suffered any time from psychological reactions, attenuated or subclinical disorder, isolated soft symptoms or personality trait leading to psychiatric help-seeking.
Since significant rate of IBS/Psy in this sample (56%), IBS could be really considered as a “special medical population” with psychiatric features: that is the point we should bear in mind when we manage and treat IBS.
IBS/Psy patients were defined by higher severity of GI symptoms particularly frequence of abdominal pain, higher severity of psychic clinical judgement, anxiety and depressive symptoms. On the other side, IBS patients with severe GI symptoms (44,6% of total sample) showed higher rate of psychiatric features (62%) which confirm, thereby, that the associated comorbidity could play a role in worsening of the disease severity.
In terms of GI symptoms, IBS/Psy complained more significantly about abdominal pain. Considering that these patiens self-assessed as more prone to somatization (headache, back pain, muscle ache, nausea etc.) we can hypothize that emotional/psychic pattern can alterate motility and visceral hypersensitivity in different parts of the GI system. However, no single pattern of disordered motility is pathognomonic of IBS. In general the alterations in GI motility likely reflect an exageration of normal pattern of response.
Evaluating the power of both GI symptoms and psychopathological features on clinical measure, self-perception and quality of life, we found that serious abdominal distress was able to significantly worsening subjective complaints (SCL-90) and quality of life (QLESQ) exclusively if associated to psychiatric comorbidity. Indeed, our data suggest that phisical distress in IBS/NoPsy is not severe and interfering with personal well-being, differently from authors who assume psychiatric symptoms as direct conseguence of irritable bowel disease.
It is likely that psychopathological features may influence the pattern of reaction to bodily stress and general satisfaction of quality of life. Such a issue could be explain
