The longitudinal course of bipolar disorder as revealed through weekly text messaging: a feasibility study

Bopp JM, Miklowitz DJ, Goodwin GM, Stevens W, Rendell JM, Geddes JR. The longitudinal course of bipolar disorder as revealed through weekly text messaging: a feasibility study.
Bipolar Disord 2010: 12: 327–334. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To examine the feasibility of collecting course of illness data from patients with bipolar I and II disorder, using weekly text‐messaged mood ratings, and to examine the time trajectory of symptom ratings based on this method of self‐report. Methods: A total of 62 patients with bipolar I (n = 47) or II (n = 15) disorder provided mood data in response to weekly cell phone text messages (n = 54) or e‐mail prompts (n = 8). Participants provided weekly ratings using the Altman Self‐Rating Mania Scale and the Quick Inventory of Depressive Symptoms–Self Report. Patients with bipolar I and II disorder, and men and women, were compared on percentages of time in depressive or manic mood states over up to two years. Results: Participants provided weekly ratings over an average of 36 (range 1–92) weeks. Compliance with the procedure was 75%. Overall, participants reported depressive symptoms 47.7% of the time compared to 7% of entries reflecting manic symptoms, 8.8% reflecting both depressive and manic symptoms, and 36.5% reflecting euthymic mood. Participants with bipolar I disorder reported more days of depression and were less likely to improve with time than participants with bipolar II disorder. Gender differences observed at the beginning of the study were not observed at follow‐up. Conclusions: The results are similar to those of other longitudinal studies of bipolar disorder that use traditional retrospective, clinician‐gathered mood data. Text‐message‐based symptom monitoring during routine follow‐up may be a reliable alternative to in‐person interviews.     

Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence

López‐Jaramillo C, Lopera‐Vásquez J, Gallo A, Ospina‐Duque J, Bell V, Torrent C, Martínez‐Arán A, Vieta E. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence.
Bipolar Disord 2010: 12: 557–567. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: To determine if the repeated occurrence of manic episodes in bipolar I disorder (BD‐I) patients is associated with reduced cognitive performance, which could in turn imply a worsening in the disorder’s evolution. Method: Cognitive performance in euthymic patients was assessed using attention, memory, and executive function tests on 24 BD‐I patients who had experienced only 1 manic episode, on 27 BD‐I patients with 2 manic episodes, on 47 BD‐I patients with 3 or more manic episodes, and on 66 healthy control subjects. Results: In BD‐I patients, number of manic episodes was positively associated with poorer performance on neurocognitive tests, an association that was not accounted for by depression, disease chronicity, onset, or medication. Significant differences in attention and executive function were found between patients and controls and in those patients who had had just 1 manic episode compared to those who had 3 or more. Conclusion: The number of manic episodes predicted poor cognitive performance, suggesting that the recurrence of mania may have a long‐term neuropsychological impact. Prospective follow‐up studies need to be completed to explore this effect further as better treatment adherence may have a protective effect on neurocognitive function.     

Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder

Brooks JO III, Bearden CE, Hoblyn JC, Woodard SA, Ketter TA. Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder.
Bipolar Disord 2010: 12: 866–874. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Reports of sustained attention deficits in the euthymic phase of bipolar disorder have been variable, and have yet to be related to cerebral metabolism. In the present study, we evaluated relationships between cognitive performance deficits and resting cerebral metabolism in euthymic older adults with bipolar disorder. Methods: Sixteen older (mean age 58.7 years) euthymic outpatients with bipolar disorder (10 type I, 6 type II; 44% female) and 11 age‐matched healthy controls received resting positron emission tomography with ¹⁸fluorodeoxyglucose and, within 10 days, the Conners’ Continuous Performance Test‐II, a commonly used measure of sustained attention and inhibitory control. Results: Bipolar disorder patients had significantly more omission errors (z = 2.53, p = 0.01) and a trend toward more commission errors (z = 1.83, p < 0.07) than healthy controls. Relative to healthy controls, among bipolar disorder subjects commission errors were more strongly related to inferior frontal gyrus [Brodmann area (BA) 45/47] hypometabolism and paralimbic hypermetabolism. In bipolar disorder subjects, relative to controls, omission errors were more strongly related to dorsolateral prefrontal (BA 9/10) hypometabolism and greater paralimbic, insula, and cingulate hypermetabolism. Conclusions: In older adults with bipolar disorder, even during euthymia, resting‐state corticolimbic dysregulation was related to sustained attention deficits and inhibitory control, which could reflect the cumulative impact of repeated affective episodes upon cerebral metabolism and neurocognitive performance. The relative contributions of aging and recurrent affective episodes to these differences in bipolar disorder patients remain to be established.     

Impulsivity across the course of bipolar disorder

Strakowski SM, Fleck DE, DelBello MP, Adler CM, Shear PK, Kotwal R, Arndt S. Impulsivity across the course of bipolar disorder.
Bipolar Disord 2010: 12: 285–297. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To determine whether abnormalities of impulse control persist across the course of bipolar disorder, thereby representing potential state markers and endophenotypes. Methods: Impulse control of 108 bipolar I manic or mixed patients was measured on three tasks designed to study response inhibition, ability to delay gratification, and attention; namely, a stop signal task, a delayed reward task, and a continuous performance task, respectively. Barrett Impulsivity Scale (BIS‐11) scores were also obtained. Patients were then followed for up to one year and reassessed with the same measures if they developed depression or euthymia. Healthy comparison subjects were also assessed with the same instruments on two occasions to assess measurement stability. Results: At baseline, bipolar subjects demonstrated significant deficits on all three tasks as compared to healthy subjects, consistent with more impulsive responding in the bipolar manic/mixed group. In general, performance on the three behavioral tasks normalized upon switching to depression or developing euthymia. In contrast, BIS‐11 scores were elevated during mania and remained elevated as bipolar subjects developed depression or achieved euthymia. Conclusions: Bipolar I disorder patients demonstrate deficits on laboratory tests of various aspects of impulsivity when manic, as compared to healthy subjects, that largely normalize with recovery and switching into depression. However, elevated BIS‐11 scores persist across phases of illness. These findings suggest that impulsivity has both affective‐state dependent and trait components in bipolar disorder.     

Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study

Chou Y‐H, Wang S‐J, Lin C‐L, Mao W‐C, Lee S‐M, Liao M‐H. Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study.
Bipolar Disord 2010: 12: 312–318. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD. Methods: Twenty‐eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery‐Åsberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight‐week period. Single photon emission computed tomography with the radiotracer ¹²³I‐ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome. Results: The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three‐way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = ?0.742, p = 0.014) only. Conclusions: Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.     

Cognitive styles in hypomanic episodes of bipolar I disorder

Lex C, Hautzinger M, Meyer TD. Cognitive styles in hypomanic episodes of bipolar I disorder.
Bipolar Disord 2011: 13: 355–364. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Cognitive vulnerability‐stress theories have recently been extended to bipolar disorder by suggesting that an activation of negative cognition might lead to depressive mood episodes and an activation of positive cognition might lead to manic mood episodes. Alternatively, the manic defense hypothesis claims that hypomanic and manic states are not the opposite of depression but rather contain similar underlying negative cognitions. The objective of this study was to further evaluate these theories by examining the cognitive patterns in bipolar I hypomania. Methods: We compared 15 hypomanic bipolar I disorder patients, 26 remitted bipolar I disorder patients, and 21 healthy individuals in a cross‐sectional study. All participants completed the Dysfunctional Attitude Scale, the Attributional Style Questionnaire, the Emotional Stroop Task, and the Emotional Auditory Verbal Learning Test. Results: Hypomanic bipolar disorder individuals showed cognitions associated with depressive states as well as cognitions associated with manic states. The results for the remitted bipolar disorder patients paralleled those for the control group. Conclusion: Dysfunctional cognition in bipolar disorder seems to relate to state rather than to trait. Hypomania includes depression‐related as well as mania‐related cognitions and can therefore not be considered as the mere opposite of depression.     

Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

State‐related alterations of gene expression in bipolar disorder: a systematic review

Munkholm K, Vinberg M, Berk M, Kessing LV. State‐related alterations of gene expression in bipolar disorder: a systematic review. Bipolar Disord 2012: 14: 684–696. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Alterations in gene expression in bipolar disorder have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state‐related alterations in gene expression have the potential to point to markers of disease activity, and trait‐related alterations might indicate vulnerability pathways. This review therefore evaluated the evidence for whether gene expression in bipolar disorder is state or trait related. Methods: A systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guideline for reporting systematic reviews, based on comprehensive database searches for studies on gene expression in patients with bipolar disorder in specific mood states, was conducted. We searched Medline, Embase, PsycINFO, and The Cochrane Library, supplemented by manually searching reference lists from retrieved publications. Results: A total of 17 studies were included, comprising 565 patients and 418 control individuals. Six studies evaluated intraindividual alterations in gene expression across mood states. Two of five studies found evidence of intraindividual alterations in gene expression between a depressed state and a euthymic state. No studies evaluated intraindividual differences in gene expression between a manic state and a euthymic state, while only one case study evaluated differences between a manic state and a depressed state, finding altered expression in seven genes. No study investigated intraindividual variations in gene expression between a euthymic state and multiple states of various polarities (depressive, manic, hypomanic). Intraindividual alterations in expression of the same genes were not investigated across studies. Only one gene (the brain‐derived neurotrophic factor gene; BDNF) was investigated across multiple studies, showing no alteration between bipolar disorder patients and control individuals. Conclusions: There is evidence of some genes exhibiting state‐related alterations in expression in bipolar disorder; however, this finding is limited by the lack of replication across studies. Further prospective studies are warranted, measuring gene expression in various affective phases, allowing for assessment of intraindividual differences.     

COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder

Soeiro‐de‐Souza MG, Machado‐Vieira R, Soares Bio D, Do Prado CM, Moreno RA. COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disord 2012: 14: 554–564. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objective: The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol‐O‐methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Methods: Seventy‐two symptomatic, medication‐free subjects with bipolar I disorder (BD‐I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Results: Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Conclusions: Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state‐dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings.     

A quantitative meta-analysis of fMRI studies in bipolar disorder

Chen C‐H, Suckling J, Lennox BR, Ooi C, Bullmore ET. A quantitative meta‐analysis of fMRI studies in bipolar disorder.
Bipolar Disord 2011: 13: 1–15. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Functional magnetic resonance imaging (fMRI) has been widely used to identify state and trait markers of brain abnormalities associated with bipolar disorder (BD). However, the primary literature is composed of small‐to‐medium‐sized studies, using diverse activation paradigms on variously characterized patient groups, which can be difficult to synthesize into a coherent account. This review aimed to synthesize current evidence from fMRI studies in midlife adults with BD and to investigate whether there is support for the theoretical models of the disorder. Methods: We used voxel‐based quantitative meta‐analytic methods to combine primary data on anatomical coordinates of activation from 65 fMRI studies comparing normal volunteers (n = 1,074) and patients with BD (n = 1,040). Results: Compared to normal volunteers, patients with BD underactivated the inferior frontal cortex (IFG) and putamen and overactivated limbic areas, including medial temporal structures (parahippocampal gyrus, hippocampus, and amygdala) and basal ganglia. Dividing studies into those using emotional and cognitive paradigms demonstrated that the IFG abnormalities were manifest during both cognitive and emotional processing, while increased limbic activation was mainly related to emotional processing. In further separate comparisons between healthy volunteers and patient subgroups in each clinical state, the IFG was underactive in manic but not in euthymic and depressed states. Limbic structures were not overactive in association with mood states, with the exception of increased amygdala activation in euthymic states when including region‐of‐interest studies. Conclusions: In summary, our results showed abnormal frontal‐limbic activation in BD. There was attenuated activation of the IFG or ventrolateral prefrontal cortex, which was consistent across emotional and cognitive tasks and particularly related to the state of mania, and enhanced limbic activation, which was elicited by emotional and not cognitive tasks, and not clearly related to mood states.     

Phenomenology associated with age at onset in patients with bipolar disorder at their first psychiatric hospitalization

OBJECTIVE: To compare the clinical presentation of patients with early-onset (age <18 years) and typical-onset (age 20-30 years) bipolar disorder at the time of first hospitalization. METHODS: Patients, aged 12-45 years at their first psychiatric hospitalization, with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were evaluated on measures of manic, depressive, and positive psychotic symptoms. Differences in symptom profiles between early- and typical-onset groups were examined. RESULTS: One hundred three early-onset and 58 typical-onset patients were compared. Mixed episodes were more common in the early-onset group, while psychotic features and current substance use were more common in the typical-onset group. There was no significant difference in manic symptom severity ratings between early- and typical-onset groups (F = 1.8, df = 11, 144, p = 0.06). However, these groups differed in depressive (F = 4.2, df = 16, 139, p < 0.001) and positive psychotic (F = 2.8, df = 16, 139, p = 0.001) symptom profiles. Typical-onset bipolar patients reported more severe weight loss and formal thought disorder compared with early-onset patients. CONCLUSIONS: Depressive and positive psychotic symptoms may differ in association with age at onset among patients with bipolar disorder. Additional studies are necessary to determine whether homogeneous phenotypes of bipolar disorder can be delineated based upon age at onset.     

Micrometer‐sized thread‐like and/or spherical particles in the first fraction of cerebrospinal fluid in patients with bipolar disorder

Båve U, Nybom R, Landén M, Wetterberg L. Micrometer‐sized thread‐like and/or spherical particles in the first fraction of cerebrospinal fluid in patients with bipolar disorder.
Bipolar Disord 2010: 12: 298–305. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Scanning electron microscopy (SEM) is a powerful tool to identify pathogenic factors for which sensitive tests are lacking. The technique has been used to recognize structures in the cerebrospinal fluid (CSF) of patients with schizophrenia. The aim of this study was to use SEM to screen for potential particles in CSF in bipolar disorder. Methods: Fresh CSF samples from 56 euthymic bipolar patients, 31 bipolar I disorder and 25 bipolar II disorder, were compared to CSF samples from 20 controls. SEM of two portions of 200 μL filtered CSF was performed; the first 0.6 mL of CSF and the following 12 mL. The microscopic structures were identified and the quantity and patterns were rated by two independent researchers. Results: Quantitative SEM examinations showed that of the 56 patients, 11 were free of any SEM structures in CSF, while 45 patients displayed morphological structures in the first 0.6 mL of CSF. By contrast, only 2 patients showed structures in the second CSF fraction drawn from the following mixed 12 mL of CSF. In total, 45 of the 56 patients had either thread‐like, spherical, or both structures in the CSF, compared to none of the 20 controls. Conclusions: The identified particles in the first fraction of CSF have previously not been described in patients with bipolar disorder. Hypothetically, the amount of SEM structures in CSF, from none to many, might correlate to the degree of the alleged underlying disease processes in the central nervous system in patients with bipolar disease.     

A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders

Background:  There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years.
Method:  Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined.
Results:  Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups.
Conclusions:  Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.     

Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder

The present study investigated possible clinical differences between bipolar patients with and without manic or hypomanic switch during antidepressant (AD) treatment. The authors undertook a retrospective assessment of 169 individuals affected by bipolar disorder type I (BP I: n=96) and II (BP II: n=73) who experienced at least one manic or hypomanic episode following depression without any interposed normothymic period ("manic switch") during AD therapy. They were compared with a sex, age (+/-5 years), and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects who have never had manic switches. Only 2 of the 169 patients had had spontaneous switches before the AD-related one. Switched subjects were marginally older (t=-2.65, df=414, P=.008) compared to not switched and less frequently delusional (chi2=13.86, P=.0002). Polarity of the onset episode was more frequently depressive in switched patients (chi2=21.93, P=.00002), which had also less previous manic episodes than not switched (t=3.44, df=332, P=.0006). Those differences were more pronounced in the BP I subsample. Switched patients were more frequently BP I (chi2=29.66; P<.00001). Maintenance with mood stabilizers appears to be a strong protective factor; in fact, of the 124 individuals undertaking a mood stabilizer therapy, 21 had a switch and 103 had no switches (chi2=41.10, P<.000001). In conclusion, some clinical variables, such as the number of manic episodes, the presence of delusions, the polarity of onset episode, and the mood-stabilizing treatment, may be involved in AD-related switches. Further studies are required to investigate the causal relationships between those factors.     

Factors associated with functional recovery in bipolar disorder patients

Wingo AP, Baldessarini RJ, Holtzheimer PE, Harvey PD. Factors associated with functional recovery in bipolar disorder patients.
Bipolar Disord 2010: 12: 319–326. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Among bipolar disorder (BPD) patients, functional recovery, defined as regaining individual premorbid residential and vocational status, is far less common than symptomatic recovery. As several factors have tentatively been implicated in outcomes in BPD, we investigated predictors of functional recovery among BPD patients, including demographic, clinical, and neurocognitive factors. Methods: We assessed functional recovery status with standardized residential and occupational indices, assessed neurocognitive functioning with performance‐based neuropsychological tests, and collected demographic and clinical information for 65 euthymic or residually depressed Structured Clinical Interview for DSM‐IV‐defined type I or II BPD patients. We examined predictors of functional recovery with multiple logistic regression modeling. Results: More education (p = 0.006), fewer years of illness (p = 0.037), and being married (p = 0.045) were associated independently with functional recovery, even after controlling for residual depressive symptoms, diagnostic type (I versus II), and psychiatric comorbidity. Functionally unrecovered BPD patients performed less well than recovered patients on verbal fluency (effect size = 0.54, p = 0.03), a measure of executive functioning, but this difference was not significant when adjusted for residual mood symptoms and education. Conclusions: Among euthymic or mildly depressed BPD patients, functional recovery was associated with more education, being married, and fewer years of illness.     

Alterations of the cerebellum and basal ganglia in bipolar disorder mood states detected by quantitative T1ρ mapping

Objectives

Quantitative mapping of T1 relaxation in the rotating frame (T1ρ) is a magnetic resonance imaging technique sensitive to pH and other cellular and microstructural factors, and is a potentially valuable tool for identifying brain alterations in bipolar disorder. Recently, this technique identified differences in the cerebellum and cerebral white matter of euthymic patients vs healthy controls that were consistent with reduced pH in these regions, suggesting an underlying metabolic abnormality. The current study built upon this prior work to investigate brain T1ρ differences across euthymic, depressed, and manic mood states of bipolar disorder.

Methods

Forty participants with bipolar I disorder and 29 healthy control participants matched for age and gender were enrolled. Participants with bipolar disorder were imaged in one or more mood states, yielding 27, 12, and 13 imaging sessions in euthymic, depressed, and manic mood states, respectively. Three‐dimensional, whole‐brain anatomical images and T1ρ maps were acquired for all participants, enabling voxel‐wise evaluation of T1ρ differences between bipolar mood state and healthy control groups.

Results

All three mood state groups had increased T1ρ relaxation times in the cerebellum compared to the healthy control group. Additionally, the depressed and manic groups had reduced T1ρ relaxation times in and around the basal ganglia compared to the control and euthymic groups.

Conclusions

The study implicated the cerebellum and basal ganglia in the pathophysiology of bipolar disorder and its mood states, the roles of which are relatively unexplored. These findings motivate further investigation of the underlying cause of the abnormalities, and the potential role of altered metabolic activity in these regions.     

Regulation of glycogen synthase kinase-3 during bipolar mania treatment

Li X, Liu M, Cai Z, Wang G, Li X. Regulation of glycogen synthase kinase‐3 during bipolar mania treatment.
Bipolar Disord 2010: 12: 741–752. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase‐3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking. Methods: This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated. Results: The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight‐week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment. Conclusions: Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.     

Altered neural function in pediatric bipolar disorder during reversal learning

Dickstein DP, Finger EC, Skup M, Pine DS, Blair JR, Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning.
Bipolar Disord 2010: 12: 707–719. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial‐and‐error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event‐related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. Method: We compared euthymic pediatric BD participants (n = 16) versus age‐, sex‐, and IQ‐matched controls (n = 16). Our main outcome measure was blood oxygen level‐dependent (BOLD) signal measured with fMRI during an event‐related probabilistic reversal task. Results: Pediatric BD participants had significantly greater neural activity than controls in fronto‐parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). Conclusions: Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.     

Impact of caregiver group psychoeducation on the course and outcome of bipolar patients in remission: a randomized controlled trial

Objective: Although there are some randomized controlled trials that highlight the positive role of family‐focused treatment added to pharmacotherapy in bipolar disorder, no trials using contemporary methodologies have analyzed the specific effect of working with caregiver‐only groups. The aim of this study was to assess the efficacy of a psychoeducational group intervention focused on caregivers of euthymic bipolar patients. Method: A total of 113 medicated euthymic bipolar outpatients who lived with their caregivers were randomized into an experimental and a control group. Caregivers in the experimental group received twelve 90‐min group psychoeducation sessions focused on knowledge of bipolar disorder and training in coping skills. The patients did not attend the groups. Caregivers assigned to the control group did not receive any specific intervention. Patients were assessed monthly during both the intervention and the 12 months of follow‐up. The primary outcome was time to any mood recurrence. Results: Psychoeducation group intervention focused on the caregivers of bipolar patients carried a reduction of the percentage of patients with any mood recurrence (χ² = 6.53; p = 0.011) and longer relapse‐free intervals (log‐rank χ² = 4.04; p = 0.044). When different types of episodes were analyzed separately, the effect was significant for both the number of patients who experienced a hypomanic/manic recurrence (χ² = 5.65; p = 0.017) and the time to such an episode (log‐rank χ² = 5.84; p = 0.015). The differences in preventing depressive and mixed episodes were not significant. Conclusions: A psychoeducation group intervention for the caregivers of bipolar patients is a useful adjunct to usual treatment for the patients in reducing the risk of recurrences, particularly mania and hypomania, in bipolar disorder.     

Morbidity in 303 first‐episode bipolar I disorder patients

Baldessarini RJ, Salvatore P, Khalsa H‐MK, Gebre‐Medhin P, Imaz H, González‐Pinto A, Perez J, Cruz N, Maggini C, Tohen M. Morbidity in 303 first‐episode bipolar I disorder patients.
Bipolar Disord 2010: 12: 264–270. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To test the hypotheses that: (i) depressive‐dysthymic‐dysphoric (D‐type) morbidity is more prevalent than manic‐hypomanic‐psychotic (M‐type) morbidity even from first episodes of bipolar I disorder (BPD‐I) and despite treatment; (ii) initial presentations predict later morbidity; (iii) morbidity varies internationally; and (iv) early and later morbidity are similar. Methods: We followed SCID‐based, DSM‐IV BPD‐I patients (n = 303) systematically and prospectively for two years to estimate the percent of weeks in specific morbid states from first lifetime major episodes. Results: Total morbidity accounted for 44% of the first two years, and D‐type exceeded M‐type illnesses by 2.1‐fold (30%/14%) among morbidities ranking: mixed states (major + minor) ≥ dysthymia ≥ mania ≥ major depression > hypomania > psychosis. In 164 cases, morbidities at 0.5–2.5 and 2.5–4.5 years were very similar. Depressive or mixed initial episodes predicted a 3.6‐fold excess of D‐type morbidity, and initial M‐type episodes predicted a 7.1‐fold excess of M‐type morbidity over two years. Morbidity in European (EU) sites was nearly half that in the U.S., and 22% greater overall among men than women. In five comparable studies, illness accounted for 54% of follow‐up time, and the ratio of D/M morbidity averaged 3.0. Conclusions: In accord with four midcourse studies, morbidity from BPD‐I onset, despite treatment by community standards, averaged 44%, was 68% D‐type morbidity, and was strongly predicted by first‐episode polarity. Lower morbidity in EU than U.S. sites may reflect differences in healthcare or social systems.