Impulsivity and phase of illness in bipolar disorder

BACKGROUND: Impulsivity is prominent in bipolar disorder, but there is little quantitative information relating it to phase of illness. METHODS: We measured impulsivity in patients with bipolar disorder who had not met episode criteria for at least 6 months, patients who were manic, and healthy control subjects. Impulsivity was measured using the Barratt Impulsiveness Scale (BIS) and performance on the computerized Immediate Memory-Remote Memory Task (IMT-DMT), based on the Continuous Performance Test, which has been shown to reflect risk of impulsivity in other populations. RESULTS: BIS scores in euthymic and manic bipolar subjects were identical, and were significantly elevated compared to controls. Commission errors (impulsive responses) on the IMT-DMT were elevated in manic subjects but were identical to controls in euthymic subjects. Measures of impulsivity did not appear related to depressive symptoms. LIMITATIONS: The number of subjects was too small for detailed investigation of the role of comorbidities; subjects were receiving pharmacological treatments. CONCLUSIONS: Impulsivity has state- and trait-related aspects in bipolar disorder.     

Cytokine profiles in bipolar affective disorder: focus on acutely ill patients

BACKGROUND: The role of the immune system in mood disorders is predominately supported by studies in unipolar major depression. However activation of the immune system has also been demonstrated in bipolar mania. Our study examines pro-inflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD). METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls. RESULTS: Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 (p < 0.001) and TNF-alpha (p < 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 (p < 0.05) and TNF-alpha (p < 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups. LIMITATIONS: A small sample size was studied. All patients remained on medication for this study. CONCLUSIONS: BPAD is associated with increased production of pro-inflammatory cytokines both in the manic and in the depressed phase as compared to healthy subjects. This is the first study, which examined both mania and bipolar depression.     

Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder

Accumulating evidence suggest that neural changes and cognitive impairment may accompany the course of bipolar disorder. Such detrimental effects of cumulative mood episodes may be related to changes in neurotrophins that take place during mood episodes but not during euthymic phases. The present study investigated serum neurotrophin-3 (NT-3) levels in patients with bipolar disorder during manic, depressed, and euthymic states, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum NT-3 levels were increased in manic (p<0.001) and depressed (p<0.001) BD patients, as compared with euthymic patients and normal controls. These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD.     

State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: A meta-analytic study

Evidence has suggested a role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of bipolar disorder (BD). Recent studies have examined BDNF levels in BD patients, but showed inconsistent results. In current study, meta-analyses by random-effects model were performed to compare blood BDNF levels between BD patients and healthy controls, and examine patients based on different affective status (manic, depressed, or euthymic state). Fifteen studies from 10 citations were included into the analysis. Pooling of results from all studies indicated that, overall, patients with BD had a lower level of BDNF than healthy controls (p = 1 × 10⁻⁴). But when separating these studies based on different affective status, it showed that the significance existed only when comparing patients in manic (p = 0.0008) or depressed (p = 0.02) state with controls, but not in euthymic state (p = 0.25). In addition, BDNF level was significantly increased after pharmacological treatment of manic state (p = 0.01). These findings indicate that BDNF levels are abnormally reduced in manic and depressed states of BD, and the reduced level in manic state increases after treatment. They suggest a role of blood BDNF level as a state-dependent biomarker of bipolar disorder.     

Plasma GABA levels in psychiatric illness

In two separate studies, we have obtained plasma levels of GABA in 134 psychiatric patients and 22 normal controls. Patients with a unipolar affective disorder had levels significantly lower than control (n = 58) as did patients with alcoholism (n = 10). Patients with a bipolar affective disorder had levels significantly higher than control when manic (n = 28) and also when euthymic on lithium prophylaxis (n = 17), but levels in the control range when depressed (n = 4). Patients with schizophrenia demonstrated a high degree of variability in their levels of plasma GABA but were not statistically different from control (n = 36). Patients with unipolar depression who received a dexamethasone suppression test had no correlation between nonsuppression of cortisol secretion and plasma levels of GABA. Diagnostic and research implication of plasma GABA in psychiatric illness are discussed.     

Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor β family, which plays a role in the development and function of hippocampal cells. Preclinical studies suggest that changes in neurotrophic growth factor systems might be involved in the pathophysiology of mood disorders including bipolar disorder (BD) [E.J. Nestler, M. Barrot, R.J. DiLeone, A.J. Eisch, S.J. Gold, L.M. Monteggia, Neurobiology of depression, Neuron 34 (2002) 13–25]. This is the first study to analyze GDNF immunocontent in BD subjects across different mood states, including mania, depression, and remission (euthymia). Fourty-four bipolar patients (14 depressed, 15 manic, and 15 euthymic) and 14 healthy controls, diagnosed according to the Structural Clinical Interview for DSM-IV were studied. Serum GDNF immunocontent was measured using Western blotting. Serum GDNF immunocontent was increased in manic (F = 42.31; p = 0.001; one-way ANOVA) and depressed (F = 42.31; p = 0.004; one-way ANOVA) bipolar patients, but not in euthymic patients as compared with controls. Our results indicate that changes in GDNF immunocontent occur during acute major affective episodes in bipolar subjects. These results further support the role of neurotrophins in the pathophysiology of bipolar disorder. Whether the observed increase in GDNF immunocontent correspond to a pathological or an adaptive response remains to be determined.     

Tritiated imipramine binding to platelets in manic subjects

We studied 21 patients with bipolar affective disorder and 25 healthy controls in order to determine if tritiated imipramine binding to platelets distinguished the manic from the depressed phase of bipolar disorder. Depressed patients had a significantly lower mean Bmax value (754 +/- 149 fmole/mg protein) than the manic and control groups (1112 +/- 248 and 1237 +/- 201 fmole/mg protein, respectively), which did not differ from each other. These differences could not be attributed to differences in age, sex, menopausal status, the presence of psychotic features or medication history among the subject groups. These findings confirm that decreased imipramine binding to platelets is a state marker for bipolar depression and not a trait marker of bipolar disorder.     

Consistency of remission and outcome in bipolar and unipolar mood disorders: a 10-year prospective follow-up

BACKGROUND: Previous studies of the natural course of bipolar disorder have suggested that relapse and psychosocial impairment are more common than many would expect during treatment under routine conditions. The present research sought to identify patterns of consistency in longitudinal recovery after an index manic or depressive episode in patients formerly hospitalized for major affective disorders. The data extend prior findings from the Chicago Follow-up Study involving four successive assessments of course and outcome for bipolar and unipolar patients over a 10-year follow-up interval. METHODS: Thirty-four RDC bipolar I manic, 17 psychotic unipolar depressed, and 72 nonpsychotic unipolar depressed patients were assessed at index hospitalization and prospectively followed-up at 2, 4.5, 7.5 and 10 years. Psychosocial functioning, rehospitalization, and overall outcome were rated by standardized instruments. Patterns of consistent remission or impairment in functioning were compared across follow-up periods. RESULTS: Consistently good functioning was observed more often among patients with unipolar nonpsychotic depression than bipolar disorder or unipolar psychotic depression. Psychosis at index hospitalization was not associated with poorer outcomes for either the bipolar or unipolar groups, although it significantly predicted psychosis at follow-up more robustly for unipolar than bipolar patients. Less than half of the bipolar cohort had good work performance at each follow-up, while unipolar nonpsychotic depressed patients had consistently better work functioning. Rehospitalization was more common for the bipolar than unipolar patients at the 4.5- and 7.5-year assessments. Sustained remission across follow-ups was associated with remission at subsequent follow-ups regardless of diagnostic polarity at index hospitalization. LIMITATIONS: The observational design, small sample size, and naturalistic treatment of subjects in this protocol prompts caution when interpreting treatment outcome findings. The availability of a bipolar cohort with relatively low attrition over a 10-year period may limit the generalizability of the current findings to patients who remain engaged in sustained contact with a long-term research program. CONCLUSIONS: Over a 10-year follow-up period, about half of bipolar patients show sustained remissions or patterns of improvement, while 30-40% experience some functional decline. The degree of consistency in remission patterns over time may hold greater prognostic significance than the polarity of an index affective episode in anticipating subsequent levels of psychosocial adjustment in severe mood disorders.     

Mismatch between self-reported quality of life and functional assessment in acute mania: a matter of unawareness of illness?

BACKGROUND: Studies addressing self-reported quality of life (QoL) in acute mania are scarce and inconsistent. While it has been suggested that there is some disagreement between objective measures and subjective QoL as reported by acutely manic patients, this issue has not been systematically studied. This study aims to investigate the self-reported QoL in manic, depressed, and euthymic BD subjects, as compared to matched healthy controls. METHODS: One-hundred and twenty type-I bipolar patients (40 manic, 40 depressed, and 40 euthymic) and 40 matched controls were studied. Self-reported QoL was assessed using the World Health Organization's Quality of Life Instrument-Short Version (WHOQOL-BREF). Objective functioning was assessed using the Global Assessment of Functioning (GAF), and depressive and manic symptoms were assessed using the Hamilton Depression Rating Scale-17 items (HDRS) and the Young Mania Rating Scale (YMRS), respectively. RESULTS: Manic patients presented the lowest GAF measures but reported same overall QoL as euthymic patients and controls, and better QoL than depressed patients. Within the manic subgroup, there was a significant inverse correlation between psychological QoL and GAF scores (r=-0.54; p=0.001). LIMITATIONS: The cross-sectional design and the lack of control for potential comorbid conditions are the major limitations of the present study. CONCLUSIONS: Our findings suggest that this mismatch between objective and subjective measures during acute mania may be associated with a lack of insight or awareness of their own illness.     

Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes

BACKGROUND: An association between social rhythm disruption (SRD) and onset of manic episodes has recently been observed. Whether other types of bipolar (depressive and cycling) or unipolar depressive episodes are similarly related to SRD is unclear, as is the association between severely threatening life events and onset of bipolar manic, depressed and cycling episodes. METHODS: Bipolar patients with purely manic (N= 21), purely depressed (N = 21) and cycling (N = 24) episodes, and 44 patients with recurrent unipolar depression, were interviewed with the Bedford College Life Events and Difficulties Schedule. The presence of severe and SRD events during the year prior to index episode onset was then determined. RESULTS: More manic than cycling and unipolar subjects experienced SRD events during 8- and 20-week pre-onset periods, and severe events during 20-week pre-onset periods. Controlling for age and prior number of episodes left most findings unchanged. An earlier finding of more manic subjects with SRD events in an 8-week pre-onset versus control period was also replicated. CONCLUSIONS: It appears that manic onsets are influenced by stressful life events, especially those involving SRD, in a unique manner compared to onsets of other types of bipolar and unipolar episodes. Onset of bipolar cycling episodes, in contrast, seems to be relatively unaffected by SRD or severe life events. These findings refine the hypothesis that SRD may precipitate onset of affective episodes to be specific to manic onsets.     

Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes

Genetic and pharmacological studies have suggested that brain-derived neurotrophic factor (BDNF) may be associated with the pathophysiology of bipolar disorder (BD). The present study investigated serum BDNF levels in manic, depressed, euthymic BD patients and in matched healthy controls, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum BDNF levels were decreased in manic (p = 0.019) and depressed (p = 0.027) BD patients, as compared with euthymic patients and controls. Serum BDNF levels were negatively correlated with the severity of manic (r = −0.37, p = 0.005) and depressive (r = −0.30, p = 0.033) symptoms. These findings further support the hypothesis that the BDNF signaling system may play a role in the pathophysiology of BD.     

Assessing personal financial management in patients with bipolar disorder and its relation to impulsivity and response inhibition

Introduction: Impulsivity and risk-taking behaviours are reported in bipolar disorder (BD). We examined whether financial management skills are related to impulsivity in patients with BD.

Methods: We assessed financial management skills using the Executive Personal Finance Scale (EPFS), impulsivity using the Barratt Impulsiveness Scale (BIS) and response inhibition using an emotional go/no-go task in bipolar individuals (N?=?21) and healthy controls (HC; N?=?23).

Results: Patients had fewer financial management skills and higher levels of impulsivity than HC. In patients and controls, increased impulsivity was associated with poorer personal financial management. Patients and HC performed equally on the emotional go/no-go task. Higher BIS scores were associated with faster reaction times in HC. In patients, however, higher BIS scores were associated with slower reaction times, possibly indicating compensatory cognitive strategies to counter increased impulsivity.

Conclusions: Patients with BD may have reduced abilities to manage personal finances, when compared against healthy participants. Difficulty with personal finance management may arise in part as a result of increased levels of impulsivity. Patients may learn to compensate for increased impulsivity by modulating response times in our experimental situations although whether such compensatory strategies generalize to real-world situations is unknown.     

Attention orienting and inhibitory control across the different mood states in bipolar disorder: An emotional antisaccade task

An antisaccade experiment, using happy, sad, and neutral faces, was conducted to examine the effect of mood-congruent information on inhibitory control (antisaccade task) and attentional orienting (prosaccade task) during the different episodes of bipolar disorder (BD) – manic (n = 22), depressive (n = 25), and euthymic (n = 24). A group of 28 healthy controls was also included. Results revealed that symptomatic patients committed more antisaccade errors than healthy individuals, especially with mood-congruent faces. The manic group committed more antisaccade errors in response to happy faces, while the depressed group tended to commit more antisaccade errors in response to sad faces. Additionally, antisaccade latencies were slower in BD patients than in healthy individuals, whereas prosaccade latencies were slower in symptomatic patients. Taken together, these findings revealed the following: (a) slow inhibitory control in BD patients, regardless of their episode (i.e., a trait), and (b) impaired inhibitory control restricted to symptomatic patients (i.e., a state)     

Predominant polarity in bipolar disorder: diagnostic implications

BACKGROUND: It has been reported that patients with bipolar disorder (BD) remain about 10 years symptomatic before the correct diagnosis is made. This fact is particularly important for patients with predominantly depressed polarity who tend to be diagnosed as suffering from unipolar major depressive disorder and treated with antidepressants. The present study was carried out to assess clinical differences between predominantly manic and depressed BD patients with a special focus on the time that patients remained undiagnosed. METHODS: Clinical and socio-demographic characteristics were obtained from a sample of 149 euthymic bipolar outpatients. Patients were divided into depressive or manic predominance of polarity. Clinical features, number of years undiagnosed (NYU) and occupational functioning were assessed in the two groups. RESULTS: Forty-five patients were classified as a "Depressive Polarity" whilst forty-seven were considered as "Manic Polarity". Depressive Polarity was associated with a longer delay to be diagnosed (F=14.43, df=89, p=0.001). The predominantly depressive patients tended to present a depressive onset of illness, earlier age of onset, longer duration of illness and higher number of suicide attempts than manic polarity patients. CONCLUSION: There was a marked clinical difference between predominantly manic and depressive bipolar patients. Predominantly depressive polarity is associated with a longer delay in receiving a correct diagnosis and effective treatment which has an important impact on the management of the illness.     

Heterogeneity in EEG sleep findings in adolescent depression: unipolar versus bipolar clinical course

Background: EEG sleep measures in child and adolescent subjects with depression have shown considerable variability regarding group differences between depressed and control subjects. This investigation was designed to assess whether some of the observed variability is related to undifferentiated unipolar and bipolar disorders in a sample that was reported previously. Methods: Twenty-eight adolescents who met criteria for unipolar major depression and 35 controls with no lifetime psychiatric disorder participated in a cross-sectional sleep polysomnography study. Approximately 7 years later, follow-up clinical evaluations were conducted in 94% of the original cohort. Clinical course during the interval period was assessed without knowledge of subjects’ initial diagnostic and psychobiological status. Re-analysis of the original sleep data were performed with the added information of longitudinal clinical course. Results: Depressed subjects who had a unipolar course showed reduced REM latency, higher REM density, and more REM sleep (specifically in the early part of the night) compared with depressed adolescents who converted to bipolar disorder and controls who remained free from psychopathology at follow-up. In contrast to the unipolar group, depressed subjects who would later switch to bipolar disorder had demonstrated more stage 1 sleep and diminished stage 4 sleep. Conclusions: These preliminary results indicate that some of the observed variability in EEG sleep measures in adolescent depression appear to be confounded by latent bipolar illness. The findings also suggest that sleep regulatory changes associated with unipolar versus bipolar mood disorders may be different.     

The impairment of pediatric bipolar sleep: hypotheses regarding a core defect and phenotype-specific sleep disturbances

BACKGROUND: The nature of the sleep disturbances associated with different phenotypes of pediatric bipolar disorder is unknown. Most manic children exhibit delayed sleep onset, but only a minority display decreased need for sleep. The DSM-IV manic sleep criterion is inadequate. METHOD: All published studies of the sleep characteristics of bipolar children and adolescents are reviewed. Relevant studies of pediatric unipolar depressed subjects, circadian variation of bipolar and sleep variables, and circadian neurobiology are also reviewed. This information forms the basis of hypotheses regarding the core defect of pediatric bipolar sleep and phenotype-specific sleep disturbances of bipolar children and adolescents. LIMITATIONS: The extant research literature is extremely limited. Interpretation of bipolar sleep is confounded by day-to-day variation of bipolar symptoms and sleep parameters, the presence of comorbid conditions, and environmental and psychosocial factors. CONCLUSIONS: The core defect of pediatric bipolar sleep is hypothesized to be a significant delay of the circadian sleep-wake cycle, a form of the delayed sleep-phase syndrome. Children and adolescents with part-day manic cycles and chronic mixed conditions typically will manifest delayed sleep onset, but not decreased need for sleep. Pediatric individuals with days-long manic cycles or chronic mania typically will manifest decreased need for sleep, produced by interaction between the sleep-onset phase delay and bedtime and early morning manic psychomotor acceleration. The sleep-onset phase delay, when expressed, is hypothesized to be a trait marker of bipolar spectrum illness. Revision of the DSM-IV manic sleep criterion is necessary.     

A pilot study of positive mood induction in euthymic bipolar subjects compared with healthy controls

BACKGROUND: Demonstrating differences between euthymic bipolar subjects and healthy controls in response to positive (happy) mood induction may help elucidate how mania evolves. This pilot study evaluates the Go task in a reward paradigm as a method for inducing a happy mood state and compares the response of euthymic bipolar subjects and healthy controls. METHOD: The Sense of Hyperpositive Self Scale, the Tellegen positive and negative adjectives, the Global-Local task and a visual analogue scale for measuring positive affect were administered to 15 euthymic bipolar subjects and 19 age-and-sex-matched healthy control subjects before and after they had performed the Go task in a reward paradigm. RESULTS: Significant differences were found between subjects and controls on several measures at each time-point but there were no differences across the groups across time except for the visual analogue scales, where subjects had a more sustained duration in self-reported happiness compared with controls. CONCLUSIONS: This pilot study has shown that a positive affect can be induced in bipolar subjects and controls which can be demonstrated by changes in scores on several tasks. However, only the visual analogue scales showed a significant difference between cases and controls over time. Such tests may prove valuable in furthering understanding about the evolution of manic mood states.     

Red blood cell NMR proton relaxation times in ill and recovered patients with unipolar and bipolar affective disorders.

Red blood cell NMR relaxation times T1 and T2 and water content were measured in ill and recovered patients with mania, unipolar depressed phase, bipolar depressed phase and control subjects. The results suggest that relaxation times are elevated in ill bipolar manic and ill unipolar depressed patients but are normal in both groups in the recovered phase and in ill bipolar depressed patients. Relaxation times therefore seem to be state-dependent but behave differently in unipolar and bipolar patients.     

Impulsivity: differential relationship to depression and mania in bipolar disorder

INTRODUCTION: Impulsivity, a component of the initiation of action, may have a central role in the clinical biology of affective disorders. Impulsivity appears clearly to be related to mania. Despite its relationship to suicidal behavior, relationships between impulsivity and depression have been studied less than those with mania. Impulsivity is a complex construct, and it may be related differently to depression and to mania. METHODS: In subjects with bipolar disorder, we investigated impulsivity in relationship to affective symptoms. Trait-like impulsivity was assessed with the Barratt Impulsiveness Scale (BIS-11). Affective symptoms were measured using the Change version of the Schedule for Affective Disorders and Schizophrenia (SADS-C). Measures were compared using analysis of variance, multiple regression and factor analysis. RESULTS: Impulsivity, as measured by the BIS, was related differentially to measures of depression and mania. Total and attentional impulsivity correlated independently with depression and mania scores. Motor impulsivity correlated with mania scores, while nonplanning impulsivity correlated with depression scores. These relationships were strongest in subjects who had never met criteria for a substance use disorder. Among manic symptoms, visible hyperactivity correlated most strongly with BIS scores, regardless of clinical state. Among depressive symptoms, hopelessness, anhedonia, and suicidality correlated most strongly with BIS scores. CONCLUSIONS: Depression and mania are differentially related to impulsivity. Impulsivity is related more strongly to measures of activity or motivation than to depressive or manic affect. The relationship between impulsivity and hopelessness may be an important factor in risk for suicide.     

Effect of symptoms on executive function in bipolar illness

BACKGROUND: The relationship between cognitive function and symptomatology in bipolar disorder is unclear. This study assessed executive function during the manic, depressed and remitted stages of bipolar I disorder. METHOD: Tasks assessing phonological and semantic verbal fluency, the Hayling Sentence Completion Test, the Stroop Neuropsychological Screening Test and the Cognitive Estimates Test were administered to manic (n = 15), depressed (n = 15), and remitted (n = 15) bipolar I patients, and to healthy controls (n = 30). Multiple regression analyses and analyses of covariance were used to identify potential determinants of executive dysfunction in the three bipolar groups. RESULTS: Executive function deficits were particularly associated with the manic state. In general, manic patients performed less accurately than the remitted and depressed groups, and their performance deficit was related to the severity of positive thought disorder. The depressed and remitted bipolar groups showed a less widespread pattern of impairment. Deficits in response initiation, strategic thinking and inhibitory control were evident in all the bipolar groups. CONCLUSIONS: Executive function deficits in bipolar I disorder are most evident during mania, and are particularly associated with formal thought disorder. However, deficits in response initiation, strategic thinking and inhibitory control may be more related to the underlying disorder than a particular symptom profile.