Cellular calcium signaling in bipolar disorder

Many discussions have been made related to diagnosis of bipolar disorder in recent years. Especially, much attention has been devoted to the activation syndrome induced by antidepressants and the bipolar spectrum disorder proposed by Gahemi. Differential diagnosis between bipolar depression and monopolar depression is extremely important when planning treatment strategy, but it is difficult to differentiate between them using symptomatic information alone. Therefore, if an easily-accessible biological marker can differentiate between them, it is expected to be extremely useful in clinical practice. Several trait biological markers associated with the pathophysiology of bipolar disorder have been identified with a high evidence level. Abnormality of cellular calcium signaling is regarded as one such replicable trait marker. Especially because human platelets are easily accessible, increasingly numerous reports describe studies of intracellular calcium concentration increase induced by various agonists in patients with bipolar disorder. Summarizing previous reports, the agonist-stimulated calcium response is enhanced significantly in patients with bipolar disorder compared to normal subjects, although resting intraplatelet calcium concentration does not differ between them. Moreover, serotonin-induced calcium response in monopolar depression and the other psychiatric diseases is not significantly different from that in normal subjects, which suggests that the enhanced calcium response to serotonin is specific to bipolar disorder among various diseases. However, several problems arise in using this marker as a supplemental tool of clinical diagnosis. First, the calcium response has a fairly common distribution between bipolar depression and monopolar depression groups although the means of the responses are significantly different. Consequently, it is difficult to differentiate clearly between bipolar depression and monopolar depression merely by setting a discriminating value. Second, it is necessary to measure calcium response as soon as possible after blood collection. Third, drugs taken at the time of blood collection might affect the calcium response. Finally little evidence exists showing whether functions in peripheral tissue actually reflect brain function. Therefore, many obstacles remain to be solved before using this marker in clinical practice.     

Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder.

Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca(2+) mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca(2+)](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BD-I patients with normal BLCL [Ca(2+)](B) (n = 8) (-42%, P = 0.003) and female BD-I patients with high [Ca(2+)](B) (n = 6) (-59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca(2+)](B) in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.     

Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder

OBJECTIVE: The authors examined the feasibility of using olfactory receptor neurons from living patients to test whether calcium signaling is altered in a neuronal cell population in bipolar disorder. METHOD: Ratiometric fluorescence photomicroscopy was used to assess basal and stimulus-induced changes in intracellular calcium levels in biopsy-derived olfactory receptor neurons from seven euthymic patients with bipolar disorder who were medication-free, 10 euthymic patients with bipolar disorder who were treated with mood stabilizers, and 17 age- and sex-matched comparison subjects without bipolar disorder. RESULTS: Olfactory receptor neurons from the seven medication-free patients responded to stimuli predominantly with decreases in intracellular calcium, unlike those from the seven matched healthy subjects. Olfactory receptor neurons from patients treated with mood stabilizers were less likely to respond to stimulation than olfactory receptor neurons from medication-free patients. CONCLUSIONS: This study demonstrates the feasibility of using olfactory receptor neurons to examine alterations in intracellular signaling in neuronal cells from living patients. Our results, although based on a small number of subjects, suggest that altered intracellular calcium signaling in olfactory receptor neurons may be a trait of bipolar disorder.     

Neuropsychological disturbances and cerebral blood flow in bipolar disorder

OBJECTIVE: To determine and correlate alterations in neuropsychological function and cerebral blood flow in bipolar patients. METHOD: Assessments included the Positive and Negative Symptom Scale, Global Assessment Functioning, Wechsler Adult Intelligence Scale (WAIS), Wisconsin Card Sorting Test (WCST), Stroop test, Trail Making Test (TMT), California Verbal Learning Test (CVLT), Wechsler Memory Scale (WMS) and phonetic verbal fluency/controlled oral word association tests. Single photon emission computed tomography (SPECT) was carried out with the administration of 99mTc-HMPAO. Forty-three outpatients out of 85 fulfilling RDC diagnostic criteria for bipolar disorder and six healthy subjects were included in the study. SPECT and neuropsychological assessments were performed in 30 patients in manic (n = 7), hypomanic (n = 8), depressed (n = 12) or euthymic (n = 3) states. All assessments were carried out before starting treatment. RESULT: Several corrected correlations between neuropsychological function and cerebral blood flow (CBF) were identified: executive function (WCST) and striatal, frontal, temporal, cerebellum, parietal and cingulate CBF; memory (WMS, WAIS-Digits) and striatal, frontal, temporal and parietal CBF; attentional tasks (Stroop) and striatal, temporo-medial and parietal CBF; verbal learning (CVLT) and frontal, posterior temporal, cingulate and occipital CBF; psychomotor disturbances (TMT) and anterior temporal CBF; poorer intelligence performance scores (WAIS-Vocabulary) and cerebellum and parietal CBF. CONCLUSIONS: This study confirms the presence of functional disturbances in fronto-subcortical structures, the cerebellum and limbic system in bipolar patients.     

Neurobiological findings in bipolar II disorder compared with findings in bipolar I disorder.

OBJECTIVE: To determine whether there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II). METHOD: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C. RESULTS: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent. CONCLUSIONS: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.     

Psychiatric disturbances in children of parents with bipolar disorder

The early symptoms of bipolar disorder in children and adolescents are often qualitatively different from the classic symptoms of mania and depression that present in adults, complicating the diagnosis of the disorder in younger populations. The focus of this article is the evaluation and treatment of children with bipolar parents who begin to develop behavioral and other psychiatric problems. The authors first review the current criteria available for diagnosing bipolar disorder in children. They consider issues related to how the DSM-IV criteria have been applied in this population, in particular the increase in the number of children diagnosed with bipolar disorder as a result of the decision to allow a "manic" episode to be diagnosed in the absence of expansive or elated mood. The practice parameters for the diagnosis and treatment of bipolar disorder in children and adolescents developed by the American Academy of Child and Adolescent Psychiatry are also discussed. The literature concerning children of parents with bipolar disorder is reviewed and indicates that these children are at increased risk for a wide range of psychiatric disorders, including bipolar disorders, other affective disorders, disruptive behavior disorders, and other psychiatric illnesses. The authors then review what is known about treatment for the early symptoms of bipolar disorder in this population and discuss the utility of mood stabilizers. The authors then discuss the role genomic screening may play in the future in identifying children at the highest risk for developing bipolar disorder. The article concludes with a summary of several endophenotypic expressions of bipolar disorder that have been described in children of parents with bipolar disorder.     

Smoking and psychosis in patients with bipolar I disorder.

We characterized 67 newly admitted patients in manic or mixed episodes of bipolar I disorder on categorical and continuous measures of smoking and psychosis to test the hypothesis that patients who were smokers would be more likely to demonstrate psychotic features. Smoking did not associate with psychosis in any of our analyses.     

The Maudsley bipolar disorder project. A survey of psychotropic prescribing patterns in bipolar I disorder

Objectives:  The outcome of Bipolar 1 Disorder (BD1) is greatly dependent on the adequacy and appropriateness of its treatment. As the treatment choices in BD1 disorder are increasing the aim of this study was to examine the current use of the pharmacological agents in BD1 patients and its association with clinical characteristics.
Methods:  Case note review of the pharmacotherapy of a sample of BD1 patients from a specified South London sector of a National Health Service Trust.
Results:  Half of the patients were on mood-stabilizers (usually lithium) and their use was associated with female gender and multiple admissions. Antipsychotics were more commonly used in patients with psychotic features and multiple manic episodes. Antidepressants were rarely prescribed alone and were not associated with increased number of manic episodes. Combination treatments were mostly used in patients in acute episodes and with multiple hospitalizations.
Conclusions:  In ordinary care, the treatment of BD1 is often driven by symptoms and falls short of the existing practice guidelines.     

Eye movement disturbances and working memory deficit in bipolar affective disorder

THE AIM AND METHODS: The aim of this study was to assess the intensity and frequency of eye movement abnormalities measured with infrared reflectometry, and working memory disturbances assessed with the Wisconsin Card Sorting Test (WCST). The study was performed in 87 patients with bipolar affective illness, in 119 patients with schizophrenia and in 90 healthy persons. In patients, the assessment was done during a mild symptomatic period or in remission. RESULTS: In patients with bipolar affective illness significant disturbances of eye movement and working memory compared with healthy subjects were found. Frequency and intensity of fixation abnormalities was less intense compared to schizophrenic patients, while smooth pursuit abnormalities had a similar degree. Working memory disturbances in bipolar patients were, as to the ability of formulation of logical conception, of similar degree as in schizophrenia. On the other hand, as to the effectiveness of thinking, no difference compared with healthy controls was found. CONCLUSIONS: The results obtained suggest that eye movement and working memory disturbances may constitute neurophysiological and neuropsychological endophenotypic markers of bipolar affective illness what makes possible using them in molecular genetic studies of this illness.     

Impaired nerve growth factor homeostasis in patients with bipolar disorder

Abstract

Objective. Neuro-trophins are critically involved in neuro-plasticity, the impairment of which is a major role-player in bipolar disorder (BD), and their altered levels have been recently advocated in the patho-physiology of this affective malady. The aim of this study, therefore, was to evaluate the plasma levels of nerve growth factor (NGF) in BD patients in comparison with control subjects. Methods. Forty-nine BD type-I individuals (30 in mania and 19 in euthymia) and 36 healthy controls were assessed by Mini-plus, Young mania and Hamilton depression rating scales. NGF levels were detected by ELISA. Results. Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania. Conclusions. This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuro-plasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state.     

Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder

The authors investigated the effect of long-term lithium administration on intracellular calcium mobilization. The subjects were 13 women with bipolar affective disorder stabilized on lithium and 12 matched healthy controls. Total and ionized serum calcium, intracellular calcium ion concentration, plasma parathyroid hormone (PTH) and tyrotropin (TSH), serum electrolytes and cyclic AMP (cAMP) activity in platelets were measured. The serum electrolytes sodium, potassium and creatinine and plasma PTH and TSH were all within normal ranges in patients and controls and no differences were found between the two groups. No difference was found in basal and prostaglandin E1 (PGE1)-stimulated cAMP generation in platelets between patients and controls. However, total serum calcium and ionized serum calcium levels were higher in patients than in controls and there was a significant correlation between these two measures. In the patient group, serum lithium concentration correlated positively with stimulated levels of intracellular calcium in platelets. In the present study, no distinct hyperparathyroidism was found in lithium-treated patients. However, our findings indicate that lithium administration affects calcium metabolism in patients with bipolar affective disorder inducing mild hypercalcemia and a dose-dependent normalized calcium mobilization. Furthermore, our results did not support the hypothesis that lithium's primary site of action in bipolar illness may be on signal transduction mechanisms.     

Neuropsychological functions in patients with bipolar I and bipolar II disorder

Objectives:  The literature reports persistent cognitive impairments in patients with bipolar disorder even after prolonged remission. However, a majority of studies have focused only on bipolar I disorder (BP-I), primarily because bipolar II disorder (BP-II) is often underdiagnosed or misdiagnosed. More attention should be paid to the differences between BP-I and BP-II, especially the aspects of neuropsychological functioning. We examined the different neuropsychological functions in BP-I and BP-II patients and compared them with those of healthy controls.
Methods:  The study included 67 patients with interepisode bipolar disorder (BP-I: n = 30; BP-II: n = 37) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function.
Results:  The BP-I group performed poorly on verbal memory, psychomotor speed, and executive function compared to the BP-II and control groups. Both bipolar groups performed significantly less well than the control group on measures of working memory and psychomotor speed, while the BP-II group showed an intermediate level of performance in psychomotor speed compared to the BP-I and control groups. There was no difference between the groups on visual memory.
Conclusions:  BP-I was characterized by reduced performance in verbal memory, working memory, psychomotor speed, and executive function, while BP-II patients showed a reduction only in working memory and psychomotor speed. Cognitive impairment existed in both subtypes of bipolar disorder, and was greater in BP-I patients. Rehabilitation interventions should take into account potential cognitive differences between these bipolar subtypes.     

The Maudsley bipolar disorder project. Clinical characteristics of bipolar disorder I in a Catchment area treatment sample.

The clinical characteristics of bipolar I disorder (BD1) have prognostic and therapeutic importance. The aim of this study was to examine the effect of demographic and clinical variables on the course of BD1. We reviewed the case notes of all BD1 patients (n = 63) receiving treatment in a London psychiatric service during a 1-month period. Depressive and manic onsets were equally likely without any gender difference. The earlier the age of onset, the more likely it was for patients to experience psychotic features. Only depressive onsets predicted a higher number of episodes of the same polarity. Male gender and substance abuse were associated with younger age at first presentation, while women with co-morbid substance abuse had more manic episodes. Male patients were more likely than females to be unemployed or single.     

Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia

Müller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL. Association between the DAOA/G72 gene and bipolar disorder and meta‐analyses in bipolar disorder and schizophrenia.
Bipolar Disord 2011: 13: 198–207. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: The d ‐amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of d ‐serine, an endogenous modulator of N‐methyl‐d ‐aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. Methods: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family‐based study design (303 core families including 916 individuals). We also conducted a meta‐analysis of DAOA/G72 polymorphisms in BD and SZ. Results: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z‐score for C‐allele = ?2.33, p = 0.02, uncorrected for genome‐wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta‐analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. Conclusions: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.