Fibromyalgia and bipolar disorder: a potential problem?

Wilke WS, Gota CE, Muzina DJ. Fibromyalgia and bipolar disorder: a potential problem?
Bipolar Disord 2010: 12: 514–520. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: To screen patients with fibromyalgia for bipolar disorder and to determine if there were any clinical clues, other than the Mood Disorders Questionnaire (MDQ), which might suggest a diagnosis of comorbid bipolar disorder. Methods: A total of 128 consecutive new fibromyalgia patients referred to a tertiary care center rheumatology practice were enrolled and assessed using a standard clinical protocol that included the completion of four screening questionnaires: (i) MDQ for bipolar disorder, (ii) Beck Depression Inventory (BDI) for depression, (iii) Epworth Sleepiness Scale (ESS) for daytime sleepiness, and (iv) Fibromyalgia Impact Questionnaire Disability Index (FIQ‐DI) to assess for functional capacity. Results: A quarter of the fibromyalgia subjects, 25.19%, had a positive screen for bipolar disorder (MDQ ≥ 7); 78.12% were clinically depressed (BDI ≥ 10); and 52.13% reported daytime sleepiness (ESS ≥ 10). Fibromyalgia subjects who screened positive for bipolar disorder had more severe depression than those with a negative screen [median BDI: 26.0 (19.0, 32.0) versus 15.0 (9.0, 24.0), p < 0.001]. Conclusions: We report a high prevalence of positive testing for bipolar disorder in this fibromyalgia cohort. Clinical data and questionnaire instruments other than nonspecific high depression severity failed to identify these patients. Since the norepinephrine serotonin reuptake inhibitors duloxetine and milnacipran have been recently approved by the U.S. Food and Drug Administration for the treatment of fibromyalgia, and because patients with bipolar disorder may experience destabilization of mood when treated with such agents, patients with fibromyalgia should be systematically screened for bipolar disorder prior to treatment.     

Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder

In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system. However, few studies have investigated molecular signaling pathways known to critically regulate inflammation. Additionally, the relationship between inflammatory function and immune cell glucocorticoid sensitivity has not been extensively explored in PTSD. Nuclear factor-κB (NF-κB) pathway activity was examined in peripheral blood mononuclear cells obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls (ages 19-48) using DNA-binding ELISA. Glucocorticoid sensitivity of monocytes in whole blood was measured as the concentration of dexamethasone needed to suppress in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production by 50% (DEX IC₅₀). Women with PTSD displayed increased NF-κB pathway activity compared to controls (t [34] = 2.45, p = 0.02) that was positively correlated with PTSD severity (determined by PTSD symptom severity scale) (r_s = 0.39, p = 0.02). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC₅₀ (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants (r = 0.66, p < 0.001). These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.     

Thought disorder in euthymic bipolar patients: a possible endophenotype of bipolar affective disorder?

The search for psychological markers or for psychological endophenotypes for bipolar affective disorder has been frustrating, and the study of neuropsychological and neurocognitive functioning may be useful in this search. This article presents the results of a study comparing Rorschach protocols from a sample of adult euthymic bipolar patients (N = 18) and matched healthy controls (N = 8). Bipolar patients showed a higher proportion of immature responses and more instances of thought disorder; patients also showed significantly more severe thought disorder. These findings are discussed in the context of 2 related previous studies. We suggest that our modest series of studies using the Rorschach Inkblot Test provides preliminary evidence that certain variables-especially the measures of thought disorder but possibly also the lack of emotional responses under cognitive "control" and the excessive proportion of immature content responses-may represent a possible endophenotype of bipolar disorder.     

Should bipolar disorder be viewed as manic disorder? Implications for bipolar depression

This paper proposes that the syndrome of mania rather than mood swings is the central distinguishing feature of bipolar disorder, which may be more appropriately viewed as manic disorder. The theoretical consequence of this change in perspective is to regard the depressive mood states as being a co-morbid condition. This may lead to a more profound and broader understanding of the variety of states of depression that complicate manic disorder. The paper also reviews diagnostic issues relating to bipolar depression. A broader approach may extend therapeutic choices, and open innovative research avenues.     

Obsessive compulsive symptoms in bipolar disorder patients: a comorbid disorder or a subtype of bipolar disorder?

概述

在过去十年中，人们越来越关注同时符合两种或两种以上精神障碍诊断标准的患者。上述共病情况之一就是双相障碍合并强迫症，这在以双相障碍为主要诊断的患者中比较常见。但是，关于这种共病的诊断和治疗的研究很少，在中国尤为如此。现有的研究主要集中在小样本的横断面研究，因此它们在对理解这种共病情况的病因和病程作用有限。对有限的文献进行回顾发现这是双相障碍中一种相对严重的、难治性的亚型，只有少数情况可以被认为是一种共病障碍。要阐明这种共病的病因、预后以及合适的治疗方法，则需要大样本的前瞻性研究。

中文全文

本文全文中文版从2015年10月26日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215091可供免费阅览下载 The Forum by Peng and Jiang[1] highlights the lack of literature about comorbid bipolar disorder and obsessive compulsive (OCD) disorder. To provide a preliminary summary of the available English-language literature, a search of PubMed using three relevant keywords (‘bipolar disorder’, ‘obsessive compulsive disorder’, and ‘comorbidity’) was conducted in July 2015. Only a few of the 176 papers retrieved by this search were directly related to the topic of interest: most of the relevant papers described the incidence and clinical features of comorbid bipolar disorder and OCD in relatively small samples of patients; some discussed the etiology and treatment of the comorbid condition; and a few reported on prospective, multi-center studies with relatively large samples. Bipolar-OCD comorbidity was first reported in a 1995 study from Germany[2] which found that more than half of all patients with bipolar disorder had experienced other mental disorders, including OCD, during the course of the bipolar disorder. The study reported that the prevalence of comorbid OCD was higher in patients with unipolar depression than among patients with bipolar disorder. A subsequent systematic review[3] of 64 relevant articles in 2014 reported that from 11 to 21% of persons with bipolar disorder experience comorbid OCD at some time during the course of their bipolar disorder. Most reports indicate that comorbid OCD exacerbates the symptoms of bipolar disorder and makes the diagnosis and treatment of bipolar disorder more difficult. Compared to OCD patients and bipolar disorder patients without other comorbid conditions, bipolar patients with comorbid OCD have: a) higher rates of obsessive ideas about sex and religion and lower rates of ritual checking;[4] b) higher rates of substance abuse (including use of alcohol, sedatives, caffeine, etc.);[5,6] more episodes of depression, higher rates of suicide, and more frequent admissions to hospitals;[7] and d) more chronic episodes and residual symptoms.[8,9] There were no differences between bipolar patients with and without comorbid OCD in age, gender, education, marital status, age of onset of bipolar disorder, personality, prevalence of psychotic symptoms or rapid cycling, history of suicide attempts, the type of initial bipolar episode (i.e., depressed or manic), and the type of episode that was most prevalent throughout the course of bipolar disorder.[9] The systematic review by Amerio and colleagues[3] found that compared to bipolar patients without comorbid OCD, patients with bipolar disorder with comorbid OCD were more likely to experience OCD symptoms during an affective disorder episode (75% v. 3%), had a higher mean (sd) number of depressive episodes (8.9 [4.2] v. 4.1 [2.7] episodes), and were more likely to experience an antidepressant-induced manic episode (39% v. 9%). They also found that among patients with comorbid bipolar disorder and OCD, OCD symptoms were more like to occur during depressive episodes than manic episodes (78% v. 64%). Based on their findings, these authors argue that the obsessive-compulsive symptoms observed in these patients were secondary to bipolar disorder, not a co-occurring independent disorder.[3] Following this logic, I recommend that the occurrence of obsessivecompulsive symptoms during the depressive (or manic) episodes of a bipolar disorder should not be sufficient to merit a diagnosis of comorbid bipolar disorder and OCD; this comorbid diagnosis should be restricted to situations in which a patient with bipolar disorder also meets the full OCD symptomatic and duration criteria when the patient is not experiencing a depressive or manic episode. There are only a few articles about the possible etiology of bipolar-OCD comorbidity. A long-term family study based on a multi-generational dataset[10] (cases registered from January 1969 to 2009 included 19, 814 with OCD, 58, 336 with schizophrenia, 48, 180 with bipolar disorders, and 14, 904 with schizoaffective disorder) found familial associations among individuals with bipolar disorder, OCD, and schizophrenia spectrum disorders. There are also few reports about the long-term prognosis of comorbid bipolar disorder and OCD. One study[11] that followed 20 patients with bipolar disorder without comorbid disorders and 20 patients with comorbid bipolar disorder and OCD for 4 years found no significant differences in the long-term outcomes between the two groups. The treatment of bipolar-OCD comorbidity is difficult because the use of antidepressants to treat obsessive compulsive disorder may induce manic episodes. The existing literature about the treatment is primarily composed of case reports, retrospective cross-sectional studies, and a few treatment studies with small samples. A recent systematic review that combined the results of four treatment studies[12] found that 42% of patients with comorbid bipolar disorder and OCD were simultaneously treated with multiple mood stabilizers and another 10% needed combined treatment with mood stabilizers and anti-psychotic medications. One of the four studies reported that the combined use of antidepressants and mood stabilizers was effective and another study reported that some patients benefitted from the combined use of mood stabilizers and psychological therapy.[11] Based on currently available information, I recommend that patients with comorbid bipolar disorder and OCD be initially treated with mood stabilizers; if mono-therapy with mood stabilizers is ineffective, adjunctive treatment with selective serotonin reuptake inhibitor antidepressants (which are less likely to induce mania) should be considered. In my opinion, the basic treatment for bipolar-OCD is mood stabilizers and could be combined with antidepressants if the patients do not respond to the single treatment (ineffective). Despite ongoing debates about the etiology, diagnosis, and treatment of comorbid bipolar disorder and OCD, the clinicians who regularly treat bipolar patients need more high-quality, evidence-based information to improve their identification and management of this relatively severe and refractory subgroup of bipolar patients. Well-designed prospective studies with relatively large samples that are specifically focused on this important subgroup of bipolar disorder patients are needed.     

Treatment with inhibitors of the NF-κB pathway improves whole body tension development in the mdx mouse

The whole body tension (WBT) method was used to evaluate the hypothesis that long term treatment with NF-κB inhibitors improves the total forward pulling tension exerted by the limb musculature of the mdx mouse. Mdx mice exhibited significantly reduced WBT values and more profound weakening during the course of generating multiple forward pulling movements than age-matched nondystrophic mice. Long term treatment with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) did not significantly reduce nuclear p65 activation in the costal diaphragm, but increased WBT by 12% in mature (12 month) mice. Daily treatment (30 days) of 1 month old mdx mice with the inhibitor ursodeoxycholic acid (UDCA) reduced costal diaphragm nuclear p65 activation by 40% and increased WBT by 21%. These results indicate that treatment with NF-κB inhibitors improves WBT in the mdx mouse and further establishes the utility of the WBT procedure in assessing therapeutic efficacy.     

Dysregulated NF-κB pathway in peripheral mononuclear cells of Alzheimer's disease patients

Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.     

Klotho dysfunction: A pathway linking the aging process to bipolar disorder?

AimAlthough accelerated aging profile has been described in bipolar disorder (BD), the biology linking BD and aging is still largely unknown. Reduced levels and/or activity of a protein named Klotho is associated with decreased life span, premature aging and occurrence of age-related diseases. Therefore, this study was designed to evaluate plasma levels of Klotho in BD patients and controls.MethodsForty patients with type 1 BD and 30 controls were enrolled in this study. After clinical evaluation, peripheral blood samples were drawn and plasma levels of Klotho were measured using enzyme-linked immunosorbent assay.ResultsPatients with BD and controls presented similar age and sex distribution. The mean ± SD length of illness was 24.00 ± 12.75 years. BD patients presented increased frequency of clinical comorbidities in comparison with controls, mainly arterial hypertension, diabetes mellitus, and hypothyroidism. Both patients with BD in remission and in mania exhibited increased plasma levels of Klotho in comparison with controls. There was no significant difference between patients in mania and patients in remission regarding the levels of Klotho.ConclusionKlotho-related pathway is altered in BD. Contrary to our original hypothesis, our sample of patients with BD presented increased plasma levels of Klotho in comparison with controls. Elevated levels of Klotho in long-term BD patients may be associated with the disorder progression. Further studies are needed to better understand the role of Klotho in BD and other mood disorders.     

Not only a bad guy:potential proneurogenic role of the RAGE/NF-κB axis in Alzheimer's disease brain

正The receptor for advanced glycation endproducts(RAGE)is a receptor of the immunoglobulin superfamily of cell surface molecules which plays important contributions under both physiological and pathological conditions.Over the years extensive research work supported the detrimental role of RAGE in Alzheimer’s disease(AD)pathophysiology,ranging from its involvement in beta amyloid(Aβ)brain influx and clearance,     

Pediatric mania: a developmental subtype of bipolar disorder?

Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged not only by case reports, but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: 1) its pattern of comorbidity may be unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder, aggression, and conduct disorder; 2) its overlap with substance use disorders; 3) its association with trauma and adversity; and 4) its response to treatment is atypical by adult standards.     

Is bipolar II a unique disorder?

The authors investigated differences between 27 outpatients who met RCD "definite" criteria for bipolar II disorder and 188 unipolar patients on several dimensions: clinical characteristics, response to acute treatment, personality profiles after recovery, and family history. The bipolar II group was found to have a higher morbid risk for depression among fathers, a greater incidence of past suicidal attempts, and a greater frequency of psychomotor retardation. A high degree of selectivity for protocol inclusion may account for the similarity seen between the bipolar II group and the unipolars on the other variables examined. The present findings suggest these two groups can be successfully combined in the treatment of recurrent depressive episodes.     

Is borderline personality disorder part of the bipolar spectrum?

In recent years, advances in the areas of both bipolar and borderline personality disorders have generated considerable interest in the clinical interface between these two conditions. Developments in the study of the neurobiology of borderline personality disorder suggest that many patients with this diagnosis have etiological features in common with those diagnosed with bipolar disorders. This claim is supported by new insights into the phenomenology of both disorders and by evidence that mood stabilizers are efficacious in the pharmacological management of borderline patients. This area of research is an important one because of the considerable morbidity and public health costs associated with borderline personality disorder. Since borderline patients can be so challenging to care for, it may be that a reframing of the disorder as belonging to the broad clinical spectrum of bipolar disorders holds benefits for patients and clinicians alike.     

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.     

What clinical features precede the onset of bipolar disorder?

Despite a growing number of reports, there is still limited knowledge of the clinical features that precede the onset of bipolar disorder (BD). To explore this, we investigated baseline data from a prospectively evaluated longitudinal cohort of subjects aged 12–30 years to compare: first, lifetime rates of clinical features between a) subjects at increased genetic risk for developing BD (‘AR’), b) participants from families without mental illness (‘controls’), and c) those with established BD; and, second, prior clinical features that predict the later onset of affective disorders in these same three groups. This is the first study to report such comparisons between these three groups (though certainly not the first to compare AR and control samples). 118 AR participants with a parent or sibling with BD (including 102 with a BD parent), 110 controls, and 44 BD subjects were assessed using semi-structured interviews. AR subjects had significantly increased lifetime risks for depressive, anxiety and behavioural disorders compared to controls. Unlike prior reports, preceding anxiety and behavioural disorders were not found to increase risk for later onset of affective disorders in the AR sample, perhaps due to limited sample size. However, preceding behavioural disorders did predict later onset of affective disorders in the BD sample. The findings that i) AR subjects had higher rates of depressive, anxiety and behavioural disorders compared to controls, and ii) prior behavioural disorders increased the risk to later development of affective disorders in the BD group, suggest the possibility of therapeutic targeting for these disorders in those at high genetic risk for BD.