Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations?

BACKGROUND: The co-occurrence of bipolar and eating disorders, though of major clinical and public health importance, remains relatively unexamined. METHODS: In reviewing the literature on this comorbidity, we compared bulimia, anorexia nervosa, bulimia nervosa, binge eating disorders and bipolar disorders on phenomenology, course, family history, biology, and treatment response. RESULTS: Epidemiological studies show an association between subthreshold bipolar disorder and eating disorders in adolescents, and between hypomania and eating disorders, especially binge eating behavior, in adults. Of the clinical studies, most show that patients with bipolar disorder have elevated rates of eating disorders, and vice versa. Finally, the phenomenology, course, comorbidity, family history, and pharmacologic treatment response of these disorders show considerable overlap on all of these parameters. In particular, on phenomenologic grounds--eating dysregulation, mood dysregulation, impulsivity and compulsivity, craving for activity and/or exercise--we find many parallels between bipolar and eating disorders. Overall, the similarities between these disorders were more apparent when examined in their spectrum rather than full-blown expressions. LIMITATIONS: Despite an extensive literature on each of these disorders, studies examining their overlap across all these parameters are relatively sparse and insufficiently systematic. CONCLUSIONS: Nonetheless, the reviewed literature leaves little doubt that bipolar and eating disorders--particularly bulimia nervosa and bipolar II disorder--are related. Although several antidepressants and mood stabilizers have shown promise for eating disorders, their clinical use when these disorders co-exist with bipolarity is still very much of an art. We trust that this review will stimulate more rigorous research in their shared putative underlying psychobiologic mechanisms which, in turn, could lead to more rational targeted treatments.     

Heritability of bipolar spectrum disorders. Unity or heterogeneity?

BACKGROUND: The purpose of this study was to investigate whether the three disorders in the bipolar spectrum, Bipolar I disorder, Bipolar II disorder and Cyclothymia, are various expressions of an underlying genetic commonality. METHOD: A sample consisting of same-sexed mono (MZ)- and dizygotic (DZ) twins were identified using hospital and outpatient registers (N=303). DSM-III-R criteria were assessed by personal interviews. Cross tabulations were used to compare concordance rates for different definitions of the bipolar spectrum. Correlations in liability and estimation of the heritability (h) with biometrical model fitting were performed. RESULTS: Concordance rates were higher among MZ- than DZ pairs for all the single diagnoses and main combinations of diagnoses. Cross-concordance between different diagnoses was observed. The heritability of Bipolar I was .73, of Bipolar I+II .77 and of Bipolar I+II+Cyclothymia .71. LIMITATION: Probands were not sampled from the general population. Most often the same person interviewed both twins in a pair. The statistical power was restricted in some sub-analyses. CONCLUSION: The 'Bipolar Spectrum' category consisting of Bipolar I disorder, Bipolar II disorder and Cyclothymia constitute one entity with high heritability without detectable shared family environmental effects. Future genetic and clinical work might consider that all variants of the bipolar spectrum are an expression of one underlying genetic liability.     

Atypical depression: a variant of bipolar II or a bridge between unipolar and bipolar II?

BACKGROUND: Although increasing data link atypical depression (AD) to the bipolar spectrum, controversies abound about the extent of the overlap. In particular, the Columbia group, which has pioneered in providing data on operational clarity and pharmacological specificity of atypical depressions, has nonetheless consistently avoided studying its discriminatory validity from bipolar II (BP-II). Accordingly, we undertook a full scale validation of such a link in a large clinical sample of BP-II and unipolar (UP) major depressive disorder (MDD). METHODS: Consecutive 348 BP-II and 254 MDD outpatients presenting with major depressive episodes (MDE) were interviewed off psychoactive drugs with a modified Structured Clinical Interview for DSM-IV, the structured Family History Screen and the Hypomania Interview Guide. We used the DSM-IV criteria for "atypical features" specifier. Depressive mixed state was defined as > or =3 concurrent hypomanic signs and symptoms during MDE. Bipolar validators were age at onset, high depressive recurrence, depressive mixed state and bipolar family history (types I and II). Univariate and multivariate logistic regression were used to examine associations and control for confounding variables. RESULTS: Frequency of AD was 43.0% in the combined BP-II and MDD sample. AD, versus non-AD, had significantly higher rates of BP-II. AD was significantly associated with all bipolar validators, among which family history was the most robust. A dose-response relationship was found between number of atypical symptoms during MDE and bipolar family history loading. The association between bipolar family history and number of atypical symptoms remained significant after controlling for the confounding effect of BP-II. Bipolar family history was strongly associated with the atypical symptoms of leaden paralysis and hypersomnia. CONCLUSION: These results confirm a strong link between AD and bipolar validators along psychopathologic and familial grounds. From a practical standpoint, AD is best viewed as a variant of BP-II. Clinicians confronted with MDE patients presenting with atypical features should strongly consider a BP-II diagnosis. In a more hypothetical vein, atypicality-or some associated features thereof-might serve as a nosologic bridge between UP and BP-II.     

Impulsive aggression with irritability and responsive to divalproex: a pediatric bipolar spectrum disorder phenotype?

BACKGROUND: The objective of this retrospective chart review was to evaluate the phenomenology and response to divalproex in a sub-population of children admitted to an inpatient setting with severe impairing symptoms of irritability and aggression. In addition, we examined whether the symptomatology of this group was consistent with a pediatric divalproex-responsive bipolar spectrum disorder. METHODS: The charts of 46 child and adolescent patients with prominent impulsive aggression with irritability admitted to a crisis stabilization center were assessed retrospectively. Impulsive aggressive symptoms were assessed for admission and discharge severity by two clinicians using the Overt Aggression Scale (OAS) and the Anger-Hostility Subscale of the SCL-90 (SCL-A), with overall functioning changes assessed using the Children's Global Assessment Scale (C-GAS). RESULTS: Statistically significant improvements were obtained for the group in the C-GAS, with significant decreases in the OAS and the SCL-A scores at discharge, following a maximal 14-day stay. No severe side effects were reported. All patients met the criteria for a potential pediatric bipolar phenotype. LIMITATIONS: This was a retrospective study without randomization or a control group. Additionally, the non-blinded design may have biased the raters concerning the effectiveness of divalproex for impulsive aggression. CONCLUSIONS: Our data are in line with divalproex response in children and adolescents with target symptoms of explosive temper and mood instability. Our data further suggest that such symptoms, coupled with impulsive aggression and irritability, as well as related manic symptoms, constitute a pediatric divalproex-responsive bipolar spectrum disorder.     

A case series on the hypothesized connection between dementia and bipolar spectrum disorders: bipolar type VI?

BACKGROUND: The concept of bipolar spectrum disorders has opened therapeutic opportunities for patients with atypical and complex affective conditions. The literature has recently described several commonalities in pathophysiological processes of bipolar disorders and dementia. However, this connection has been insufficiently appreciated at the clinical level, in part because affective dysregulation in the elderly and, particularly in the dementia setting, is typically attributed either to secondary depressive states or otherwise relegated to a neurologically understandable behavioral complication resulting from cerebral disease. METHODS: We selected a case series of 10 elderly patients with late-onset mood and related behavioral symptomatology and cognitive decline without past history of clear-cut bipolar disorder. Clinical features, temperament, cognition, family history and pharmacological response were assessed to identify prototypical patients to illustrate the complexities of the dementia-bipolar interface. RESULTS: Mixed and depressive mood symptoms were most commonly observed and all patients had been premorbidly of hyperthymic, cyclothymic and/or irritable temperaments. Most patients had a family history of bipolar disorder or disorders related to the bipolar diathesis. Symptoms were often refractory to or aggravated by antidepressants and acetylcholinesterase inhibitors, whereas mood stabilizers and/or atypical antipsychotics were beneficial, promoting behavioral improvement in all treated patients and marked cognitive recovery in five. LIMITATIONS: Case series with retrospective methodology. CONCLUSION AND CLINICAL IMPLICATIONS: Patients with cognitive decline and frequent mood lability might be manifesting a late-onset bipolar spectrum disorder, which we posit as type VI. We further posit that dementia and/or other biopsychosocial challenges associated with aging might release latent bipolarity in such individuals. Antidepressants, even drugs targeting dementia, might aggravate the behavioral dysregulation in these patients. Evaluation of premorbid temperament and/or family history of bipolarity and related disorders might help in broadening the clinical and biological understanding of such patients, providing a rationale for better customized treatment along the lines of mood stabilization and avoidance of antidepressants.     

Hypochondriasis and somatization: two distinct aspects of somatoform disorders?

We investigated boundaries and overlap between somatization and hypochondriasis on different levels of psychopathology: (1) comorbidity between hypochondriasis and somatization on the level of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994): (2) comorbidity with other mental disorders; (3) differences in clinical characteristics: and (4) overlap on the level of psychometric measures. The sample consisted of 120 psycho somatic inpatients. Somatoform, hypochondriacal, and depressive symptomatology, cognitions about body and health, and further aspects of general symptomatology were investigated. Diagnoses of Axis I and II were based on DSM-IV Our results suggest a large overlap on the level of DSM-IV-diagnoses: only 3 of 31 hypochondriacal patients had no multiple somatoform symptoms, while 58 of 86 patients with multiple somatoform symptoms had no hypochondriasis. However, the overlap between hypochondriacal and somatization symptomatology on the level of psychometric measurement is only moderate, indicating that hypochondriasis is a markedly distinct aspect of somatoform disorders.     

A distinct microvascular pattern accompanied by aggressive clinical course in breast carcinomas: A fact or a coincidence?

The aim of this study was to evaluate the potential relationship of microvascular growth patterns with survival in invasive breast carcinomas.     

Synaptic,intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders?

Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.     

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum,genotype–phenotype correlations,and molecular basis

PurposeSifrim–Hitz–Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype–phenotype correlations, and the effect of different missense variants on CHD4 function.MethodsWe collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.ResultsThe majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype–phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.ConclusionThe CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.     

Validating 'hard' and 'soft' phenotypes within the bipolar spectrum: continuity or discontinuity?

The unitary Kraepelian concept of manic-depressive illness which incorporated attenuated forms, personal dispositions to mood instability, as well as much of the terrain of remitting depressions, may be considered by many to be too broad. On the other hand, the presently preferred unipolar-bipolar dichotomy in official nosology fails to account for the very common occurrence of clinical and subclinical conditions in the interface of major depressive disorders and bipolarity. The emerging concept of the bipolar spectrum represents a provocative working hypothesis to account for these conditions.     

Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups?

Meckel syndrome (MKS) is a lethal malformation syndrome that belongs to the group of disorders that are associated with primary cilia dysfunction. Total of five genes are known to be involved in the molecular background of MKS. Here we have systematically analyzed all these genes in a total of 29 MKS families. Seven of the families were Finnish and the rest originated from elsewhere in Europe. We found 12 novel mutations in 13 families. Mutations in the MKS genes are also found in other syndromes and it seems reasonable to assume that there is a correlation between the syndromes and the mutations. To obtain some supportive information, we collected all the previously published mutations in the genes to see whether the different syndromes are dictated by the nature of the mutations. Based on this study, mutations play a role in the clinical phenotype, given that the same allelic combination of mutations has never been reported in two clinically distinct syndromes. © 2009 Wiley‐Liss, Inc.     

Early and late onset bipolar disorders: two different forms of manic-depressive illness?

BACKGROUND: Conflicting results in genetic studies of bipolar disorders may be due to the clinical and genetic heterogeneity of the disease. Age at onset of bipolar disorders may be a key indicator for identifying more homogeneous clinical subtypes. We tested whether early onset and late onset bipolar illness represent two different forms of bipolar illness in terms of clinical features, comorbidity and familial risk. METHODS: Among a consecutively recruited sample of 210 bipolar patients, we compared early onset (n=58) and late onset (n=39) bipolar patients; the cut-off points were age at onset before 18 years and after 40 years for the two subgroups. The subgroups were compared by independent t tests and a contingency table by raw chi-square test. Morbid risk among first-degree relatives was measured by the survival analysis method. RESULTS: The early onset group had the most severe form of bipolar disorder with more psychotic features (P=0.03), more mixed episodes (P=0.01), greater comorbidity with panic disorder (P=0.01) and poorer prophylactic lithium response (P=0.04). First degree relatives of early onset patients also had a higher risk of affective disorders (P=0.0002), and exhibit the more severe phenotype, i.e bipolar disorder. CONCLUSION: Our data suggest that early and late onset bipolar disorders differ in clinical expression and familial risk and may therefore be considered to be different subforms of manic-depressive illness.     

Prevalence of Acanthamoeba and superbugs in a clinical setting: coincidence or hyperparasitism?

Antibacterial strategies to eradicate superbugs from hospitals/nursing homes have had limited success, suggesting the need for employing innovative preventative measures and better understanding of the prevalence of microbial pathogens in close proximity of susceptible populations. A total of 120 environmental samples were collected from the Aga Khan University hospital. Amoebae were identified using morphological characteristics as well as PCR using genus-specific primers, while bacteria were identified using standard biochemical testing. Out of 120 samples tested, 52 (43.3 %) samples were positive for Acanthamoeba, while all 120 (100 %) samples were positive for bacteria. Following bacterial identification, samples showed mixed bacterial populations. Out of 120 samples, 76 (63.3 %) samples were positive for Bacillus spp., 64 (53.3 %) samples were positive for Corynebacterium spp., 32 (26.6 %) samples were positive for Staphylococcus spp., and 9 (7.5 %) samples were positive for Micrococcus spp. The antibiotic susceptibility showed that all bacterial isolates recovered were multiple drug-resistant. The current findings suggest that Acanthamoeba and bacteria coexist in a clinical environment. Given that Acanthamoeba can harbor bacteria, anti-amoebic approaches may represent a strategy in eradicating “superbugs” from the clinical setting in addition to the current measures.     

Bacteremic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis: a single or two distinct clinical entities?

The phenotypically indistinguishable Acinetobacter baumannii and Acinetobacter nosocomialis have become leading pathogens causing nosocomial pneumonia in critically ill patients. A. baumannii and A. nosocomialis nosocomial pneumonias were grouped as a single clinical entity previously. This study aimed to determine whether they are the same or a different clinical entity. A total of 121 patients with A. baumannii and 131 with A. nosocomialis bacteremic nosocomial pneumonia were included during an 8-year period. Despite the similar Charlson co-morbidity scores at admission, patients with A. baumannii pneumonia were more likely to have abnormal haematological findings, lobar pneumonia, significantly higher Acute Physiology and Chronic Health Evaluation II scores and higher frequency of shock at the onset of bacteraemia than those with A. nosocomialis pneumoni. A. baumannii isolates were resistant to more classes of antimicrobials, except colistin, and therefore the patients with A. baumannii pneumonia were more likely to receive inappropriate antimicrobial therapy. The 14-day mortality was significantly higher in patients with A. baumannii pneumonia (34.7% vs. 15.3%, p 0.001). A. baumannii was an independent risk factor for mortality (OR, 2.03; 95% CI, 1.05–3.90; p 0.035) in the overall cohort after adjustment for other risk factors for death, including inappropriate antimicrobial therapy. The results demonstrated the difference in clinical presentation, microbial characteristics and outcomes between A. baumannii and A. nosocomialis nosocomial pneumonia, and supported that they are two distinct clinical entities.     

Facial hemangioma and malformation of the cortical development: a broadening of the PHACE spectrum or a new entity?

Facial hemangioma is usually isolated but its association with craniocervical arterial anomalies and structural brain malformations is well known. The acronym PHACE syndrome (posterior fossa malformation, facial hemangiomas, arterial anomalies, cardiac/aortic anomalies, and eye abnormalities) has been used to indicate that disorder in which brain anomalies are mainly represented by the Dandy-Walker malformation. We report on a 10-month-old boy affected by facial hemangioma and a complex cortical dysplasia located in the left frontal region. The lesion was characterized by a deeply infolding pachygyric cortex and a band of gray matter lining the wall of the lateral ventricle. The entire left cerebral hemisphere appeared hypoplastic. No anomalies of the posterior fossa structures or cardiac/aortic malformations were present. An overlapping clinical/pathological pattern was previously reported in another patient with facial hemangioma and cerebrovascular anomalies. These observations seem to indicate that the facial hemangiomas may be associated with disorders of the cortical development.