Bipolar Disorder Subjects Research Articles

Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.

We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.

Is lithium response related to G sα levels in transformed lymphoblasts from subjects with bipolar disorder?

Background: A series of studies from independent laboratories have found increased levels of G sα in bipolar disorder in postmortem brain and peripheral blood cells. Long-term lithium administration blunts G-protein coupled cAMP signaling and may regulate G sα levels. Methods: We measured G sα in transformed lymphoblasts obtained from subjects with bipolar disorder and compared the findings with 23 age- and sex-matched controls. To reduce patient heterogeneity, we included only patients with an excellent response to lithium prophylaxis. Results: We found no differences in G sα protein levels measured with immunoblotting. G sα levels did not correlate with age, age of onset or duration of lithium therapy. Limitations: This study made use of transformed lymphoblasts, which may not fully represent changes that occur in regionalized brain tissue. Furthermore, the transformed lymphoblasts used in this study were acquired from a select group of bipolar disorder subjects that responded to lithium treatment. Lastly, consideration has to be given to the small sample size of the study. Conclusions: These results are consistent with recent observations suggesting that mood state and treatment effects may account at least in part for increased G sα levels in bipolar disorder. Clinical relevance: This study suggests a need to further characterize biological phenotypes in subjects with mood disorders to enhance genetic studies.

Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder

This project was designed to compare differences in brain proton spectra between children and adolescents with bipolar disorder (BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol levels following lithium therapy, utilizing in vivo proton magnetic resonance spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior cingulate cortex for acquisition of the 1H spectra at baseline and after acute (7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed with BPD, and in 11 normal controls. Acute lithium treatment was associated with a significant reduction in the myo-inositol/creatine ratio. This decrement was also significant in lithium-responders when analyzed separate from non-responders. Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine during the manic phase. These preliminary data provide evidence that a significant reduction in anterior cingulate myo-inositol magnetic resonance may occur after lithium treatment, especially among responders. Follow-up studies involving a larger sample may allow us to confirm whether changes in myo-inositol associated with acute lithium therapy persist in long-term clinical response of patients with and without lithium compliance.

Comorbidity of obsessive-compulsive disorder in recovered inpatients with bipolar disorder.

To determine the frequency of obsessive-compulsive disorder (OCD) in inpatient subjects with bipolar disorder (BD) and to examine the clinical characteristics of BD subjects with OCD. The sample consisted of 143 inpatient subjects with DSM-III-R BD-I and BD-NOS (BD-II), recovered from a current episode of either depression or mania. Demographic and clinical variables were obtained on the day of admission. Current comorbid conditions including OCD were determined by the Structured Clinical Interview for DSM-III-R Ifollowing recovery from the acute affective episode. The frequency of current OCD was 7% (N = 10). All BD subjects with OCD were BD-II, were male, and had a diagnosis of current dysthymia. They had fewer episodes and a higher incidence of prior suicide attempts than bipolar subjects without OCD. None of the bipolar subjects with OCD fulfilled criteria for cyclothymia. Our findings suggest that BD-II, OCD, dysthymia, and suicidality cluster together in some subjects with BD. We discuss the clinical implications of our findings.

Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder

Background: N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ( 1H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo 1H MRS. Methods: We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using 1H MRS. Results: DLPF NAA/Cr-PCr ratios were lower on the right hemisphere( p < .03) and the left hemisphere ( p < .003) in bipolar disorder patients compared with healthy control subjects. Conclusions: These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region.

Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder.

Previous observations of reduced [3H]cyclic AMP binding in postmortem brain regions from bipolar affective disorder subjects imply cyclic AMP-dependent protein kinase function may be altered in this illness. To test this hypothesis, basal and stimulated cyclic AMP-dependent protein kinase activity was determined in cytosolic and particulate fractions of postmortem brain from bipolar disorder patients and matched controls. Maximal enzyme activity was significantly higher (104%) in temporal cortex cytosolic fractions from bipolar disorder brain compared with matched controls. In temporal cortex particulate fractions and in the cytosolic and particulate fractions of other brain regions, smaller but statistically nonsignificant increments in maximal enzyme activity were detected. Basal cyclic AMP-dependent protein kinase activity was also significantly higher (40%) in temporal cortex cytosolic fractions of bipolar disorder brain compared with controls. Estimated EC50 values for cyclic AMP activation of this kinase were significantly lower (70 and 58%, respectively) in both cytosolic and particulate fractions of temporal cortex from bipolar disorder subjects compared with controls. These findings suggest that higher cyclic AMP-dependent protein kinase activity in bipolar disorder brain may be associated with a reduction of regulatory subunits of this enzyme, reflecting a possible adaptive response of this transducing enzyme to increased cyclic AMP signaling in this disorder.

Clinical characteristics of bipolar disorder subjects with large CAG/CTG repeat DNA

Background: Unstable DNA has been implicated in a variety of neuropsychiatric disorders, with increasing severity of disease associated with larger DNA repeats. We examined the unstable DNA hypothesis for bipolar disorder by looking for increased severity of symptoms and earlier age of onset amongst bipolar individuals with large CAG/CTG repeats. Methods: From a sample of 91 bipolar subjects, eight with large CAG/CTG (≥270bp) trinucleotide repeats were matched to eight bipolar individuals with small repeats (≤150bp). Medical charts were reviewed for age of onset and a number of severity indicators. Candidate CAG/CTG expansions on chromosomes 17 and 18 were also genotyped. Results: No obvious differences were noted for the clinical indices, however seven out of eight individuals with large Repeat Expansion Detection (RED) products had expansions at the CTG18.1 locus, while four out of eight had large repeats at ERDA1. Both of these sites are unlikely to be related to disease. Limitations: Our total sample size is small and less than 9% have large repeats. Conclusions: The lack of increased severity or earlier age of onset amongst bipolar subjects with large CAG/CTG repeats suggests these repeats are unlikely to have a major etiological role in bipolar disorder.

G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death.

Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature.

Platelet Protein Kinase C alpha Levels in Drug-Free and Lithium-Treated Subjects with Bipolar Disorder

Recent studies suggest that protein kinase C (PKC), particularly the α isoform, plays an important role in the action of lithium. There is, however, little evidence from patients with bipolar disorder (BD) to support this effect. The present investigation carried out comparative studies of PKC levels in platelets obtained from BD subjects including those with and without lithium treatment. All subjects met DSM-IV criteria for BD type I confirmed by structured interview (SCID-IV). Levels of PKC-α isoform in platelets from controls and from BD subjects were measured with immunoblotting analysis. No significant differences were found between controls, drug-free or lithium-treated BD subjects on membrane or cytosolic levels of PKC-α or in the membrane-to-cytosol ratio of this protein. The present study suggests that levels of PKC-α do not change in the peripheral tissues of BD subjects with or without lithium treatment.

Abnormalities of Cyclic Adenosine Monophosphate Signaling in Platelets From Untreated Patients With Bipolar Disorder

Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects. Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging. The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons. Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.

Glycogen synthase kinase-3beta, beta-catenin, and tau in postmortem bipolar brain.

Therapeutic concentrations of the anti-bipolar drug lithium inhibit the activity of glycogen synthase kinase-3beta, which raises the possibility that this enzyme and its substrates may be altered in the brain of subjects with bipolar disorder. Therefore, in prefrontal cortical samples from subjects with bipolar disorder and age-matched control subjects, we examined the levels of glycogen synthase kinase 3beta and of two proteins modified by it, beta-catenin and the microtubule associated protein tau. There were no significant differences between subject groups among these measurements, but there was a tendency for the tau isoform profile to be modified in bipolar tissue. Thus, while there are no differences between bipolars and controls in prefrontal cortical levels of glycogen synthase kinase-3beta, beta-catenin, or tau, tau isoform levels or phosphorylation states may be modified in bipolar disorder.

Genetic association analysis of serotonin system genes in bipolar affective disorder.

This study examined the putative role of serotonin genes in the etiology of bipolar affective disorder. Genetic association analysis was performed for individuals with bipolar affective disorder and unaffected subjects closely matched in age, sex, and ethnic background (N=103 in each group). The allele and genotype frequencies of polymorphisms at the genes for serotonin receptors HTR1A, HTR1Dalpha, HTR1Dbeta, HTR2A, HTR2C, HTR7, tryptophan hydroxylase (TPH), and the serotonin transporter (hSERT) were compared in the two groups of subjects. Statistically significant positive associations were found for HTR2A and hSERT polymorphisms. However, results from an independent replication group of over 100 patients with bipolar affective disorder and their matched comparison subjects failed to confirm these associations. These results suggest that the serotonin genes studied are not associated with bipolar affective disorder, although transmission disequilibrium studies are required in order to confirm this conclusion.

Quality of life and lifestyle disruption in euthymic bipolar disorder

The objective was to assess the extent and pattern of illness intrusiveness, one measure of quality of life, in subjects with bipolar disorder (BD) and to determine whether specific illness variables had influenced the degree of intrusiveness experienced. To compare findings from BD subjects relative to published findings for subjects with chronic medical conditions. The study involved the administration of a self-report assessment tool to euthymic outpatients with BD attending a university based hospital clinic. Of the 155 eligible participants, 112 completed a standardized psychiatric interview (SADS-L) and 87 of these met study criteria for euthymia and were approached to participate in the study. Sixty-eight completed self-report measures were returned. The main outcome measure was the Illness Intrusiveness Rating Scale (IIRS) which was analysed along with a composite measure of life events. It resulted that individuals' with BD experience significant illness intrusiveness into a number of life domains even after controlling for negative life events. Factors such as type of BD, the presence of a depressive episode in the preceding year and current Hamilton depression rating scale score contributed to the total illness intrusiveness. The degree of total illness intrusiveness experienced by individuals with BD was similar to that of subjects with multiple sclerosis and greater than subjects with end stage renal disease and rheumatoid arthritis. It seems apparent that quality of life, as determined by illness intrusiveness, is compromised in subjects with BD even during periods of euthymia. BD is at least as intrusive as several chronic medical conditions. Those with a type II BD report greater impairment in all domains compared with type I. Future research should determine specific psychosocial interventions aimed at reducing the impact of BD.

The niacin challenge test: Clinical manifestation of altered transmembrane signal transduction in schizophrenia?

Several lines of evidence implicate altered phospholipid-dependent signal transduction (PDST) in the pathophysiology of schizophrenia. Niacin induces vasodilation through mechanisms requiring intact PDST. Thus, an altered response to a challenge dose of niacin may reflect disturbances in these signalling processes in this disorder. In the present study, niacin-induced vasodilation was estimated quantitatively in schizophrenic and comparison bipolar affective disorder and healthy subjects using thermocouple sensors to measure the change in skin temperature relative to core body and ambient room temperature. Twelve (42.9%) of 28 schizophrenic subjects did not vasodilate in response to a 200-mg niacin challenge dose, whereas only 1 of 18 (6%) bipolar disorder subjects and none of 28 controls showed impaired response (Fisher's Exact Test, p < .0001). These findings support the notion that the schizophrenic syndromes are biochemically heterogeneous and suggest the existence of a subgroup of schizophrenic subjects in whom phospholipid-dependent signalling responses may be impaired.

Stimulatory G-protein alpha-subunit mRNA levels are not increased in autopsied cerebral cortex from patients with bipolar disorder.

Increased alpha-subunit (alpha s) levels of both the 45- and 52-kDa isoforms of the stimulatory guanine nucleotide binding protein (G-protein), have been found in postmortem brain and mononuclear leukocytes from patients with bipolar disorder (BD). The pathophysiological mechanism responsible for increased alpha s protein levels is unknown, however, it may involve increased expression of the gene encoding this protein. To assess this possibility, alpha s mRNA levels were determined by RT-PCR in postmortem brain from 10 subjects with an antemortem diagnosis of BD and age- and sex-matched control subjects in whom we had previously reported increased alpha s protein levels. There were no significant differences in alpha s mRNA levels in frontal, temporal, or occipital cortex between BD and control subjects. Cerebral cortex alpha s mRNA levels did not correlate with age or postmortem interval. These findings do not support the notion that higher alpha s levels found in BD postmortem brain are a result of increased gene expression.

Enhanced protein kinase C activity and translocation in bipolar affective disorder brains

Protein kinase C (PKC) activity and its redistribution were determined in the frontal cortices of postmortem brains of bipolar affective disorder subjects and age-, sex-, and postmortem time-matched controls. Membrane and cytosolic PKC activity was determined by histone phosphorylation using [32P]-adenosine triphosphate as substrate. Specific PKC isozyme levels were assessed by Western blot analysis using antipeptide antibodies. Brain membrane-associated PKC activity was higher in bipolar vs. control tissue. An examination of the specific PKC isozymes in cortical homogenates revealed that cytosolic alpha- and membrane-associated gamma- and zeta PKC isozymes were elevated in cortices of bipolar affective disorder subjects, whereas cytosolic epsilon PKC was found to be reduced. In control brain slices, incubation with 1 mumol/L phorbol 12-myristate 13-acetate (PMA) caused an increase in membrane PKC activity, whereas cytosolic enzyme activity was decreased. This redistribution of the enzyme by PMA was markedly potentiated in brain slices of bipolar subjects. The results suggest that PKC-mediated phosphorylation is increased in brains of subjects with bipolar affective illness.

Receptor‐Mediated Activation of G Proteins Is Increased in Postmortem Brains of Bipolar Affective Disorder Subjects

Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor-mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age-, sex-, and postmortem interval-matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5'-O-(3-[35S]thiophosphate) ([35S]GTP gamma S) binding to specific G alpha proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTP gamma S to the G alpha proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa G alpha S proteins but no changes in the amounts of G alpha i, G alpha o, G alpha Z, G alpha q/11, or G beta proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)-activated ADP-ribosylations of G alpha i and G alpha o were enhanced by approximately 80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin-induced, magnesium-dependent reduction in PTX-mediated ADP-ribosylation of G alpha i/G alpha o in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor-G protein coupling in bipolar brain membranes. In addition, the amounts of G beta proteins that coimmunoprecipitated with the G alpha proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor-G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder.

13. - Enhanced transmembrane signaling of 5-HT receptor in platelets of bipolar affective disorder subjects

13. - Enhanced transmembrane signaling of 5-HT receptor in platelets of bipolar affective disorder subjects

Evidence of chaotic mood variation in bipolar disorder.

Using long-term daily mood records obtained from patients with bipolar disorder and normal subjects, we sought to determine the temporal pattern of mood in bipolar disorder. Time series of 1.0 to 2.5 years from seven rapid-cycling patients with bipolar disorder and 28 normal controls were obtained. These were evaluated with several techniques to identify whether the temporal pattern of mood originates from a periodic, a random, or a deterministic source. True cyclicity was not apparent in the power spectra of either the normal subjects or the patients with bipolar disorder. Instead, spectra with a broadband "l/f" shape were observed in both groups, and these spectra were significantly flatter in normal subjects (P = .02). Correlation dimension estimates are a measure of nonlinear deterministic structure, and convergent estimates could be obtained for six of the seven patients with bipolar disorder and none of the normal subjects (P < .001). Additional findings are consistent with these results. These studies indicate that mood in patients with bipolar disorder is not truly cyclic for extended periods. Nonetheless, self-rated mood in bipolar disorder is significantly more organized than self-rated mood in normal subjects and can be characterized as a low-dimensional chaotic process. This characterization of the dynamics of bipolar disorder provides a unitary theoretical framework that can accommodate neurobiologic and psychosocial data and can reconcile existing models for the pathogenesis of the disorder. Furthermore, consideration of the dynamical structure of bipolar disorder may lead to new methods for predicting and controlling pathologic mood.

Altered platelet protein kinase C activity in bipolar affective disorder, manic episode

Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.