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.     

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.     

The precipitants of manic/hypomanic episodes in the context of bipolar disorder: a review

Background

Mania/hypomania is the hallmark feature of bipolar disorder. This paper aims to review the current evidence in relation to factors hypothesised to precipitate bipolar mania/hypomania, and suggest areas for future research.

Methods

A selective review of original and review papers was conducted. The electronic databases ‘PsycINFO’ and ‘PubMed’ were searched using the following search strings: “bipolar disorder” or “mania” or “hypomania” or “manic-depression” with “triggers” or “precipitants” or “precedents” or “predictors”.

Results

There is evidence that goal attainment events, antidepressant medication, disrupted circadian rhythms, spring/summer seasonal conditions, and more tentatively, stressful life events and high emotional expression, may precipitate bipolar mania/hypomania in susceptible individuals. Evidence from case reports and clinical observations are also reported.

Discussion

The pathways to bipolar mania/hypomania may be many and varied, and many of these pathways may be outside the awareness of individuals with bipolar disorder. Greater awareness of the broad number of precipitating factors is needed to inform self-management and psycho-educational programs to build resilience to further episodes. Future research is needed to explore what other factors may precipitate bipolar mania/hypomania, and to determine why some factors may precipitate mania/hypomania in some individuals with bipolar I or II disorder but not in others.     

Course sequences in bipolar disorder: Depressions preceding or following manias or hypomanias

Background

Inferior response to lithium treatment has been reported in bipolar disorder (BD) patients with mania or hypomania following episodes of major depression (DMI) versus preceding depression (MDI), with intervening euthymic periods. However, additional characteristics of BD course-patterns require further assessment.

Methods

We reviewed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences.

Results

Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals. Prevalent sequences included: major depression–hypomania (15.0%), mania–major depression (14.6%), major depression–mania (11.6%), and rapid-cycling (9.6%). Among subjects grouped by course-sequences (based on mania, mixed-states, or hypomania and major or minor depression), depression-before-[hypo]mania (DMI) cases were more likely to be women, diagnosed BD-II, have first-episodes of depressive or anxiety disorder, spend more time ill in depression, and benefit less with long-term mood-stabilizing treatments than with the opposite pattern (MDI). MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments. Meta-analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29% [CI: 18–40%] (p<0.0001).

Limitations

Some data were retrospective and subject to recall bias, and treatment was clinical (non-randomized).

Conclusions

The DMI course was strongly associated with first-episode depression or anxiety, excess depressive morbidity, and inferior treatment response, especially for depression.     

Mood state dependency of dysfunctional attitudes in bipolar affective disorder

Introduction. Studies of cognitive styles among euthymic people with bipolar affective disorder (BAD) without use of mood induction techniques to access those cognitive styles give misleading impressions of normality of those cognitions. The aim of this study was to assess dysfunctional attitudes of participants with BAD, and control participants with no previous psychiatric histories, after mood inductions.

Methods. Sad and happy moods were induced within 49 BAD and 37 controls. Dysfunctional attitudes were measured following mood inductions using the Dysfunctional Attitude Scale—short form (DAS-24), which has three subscales of achievement, interpersonal, and goal attainment.

Results. It was hypothesised that within BAD the sad mood induction would help in accessing dysfunctional attitudes in all three domains relative to the happy mood induction. This was supported. It was also hypothesised that the mood inductions would not affect dysfunctional attitudes within controls. This was supported. When diagnosis was entered as a between group variable, achievement dysfunctional attitudes were significantly higher in BAD compared to controls after a happy induction.

Conclusions Both sad and happy moods provoked higher levels of dysfunctional attitudes within BAD. Euphoria may be related to elevated achievement dysfunctional attitudes, raising risk for mania.     

Trace elements in manic depressive psychosis

The concentrations of 16 elements (Al, Ba, Br, Ca, Cl, Cu, I, Pb, Mg, Mn, Mo, Rb, Se, Na, S and Ti) were estimated by neutron activation analysis in samples of hair, whole blood, serum and urine from normal controls, from patients suffering from mania and depression and from patients who had recovered from mania and from depression. Significant differences between groups were shown but apart from molybdenum, no element showed a significant change in more than one tissue. The differences in molybdenum concentrations appear to be of potential interest but the results must be interpreted with caution.     

Group cognitive behavior therapy for bipolar disorder can improve the quality of life

Bipolar disorder (BD) can have an impact on psychosocial functioning and quality of life (QoL). Several studies have shown that structured psychotherapy in conjunction with pharmacotherapy may modify the course of some disorders; however, few studies have investigated the results of group cognitive behavior therapy (G-CBT) for BD. Our objective was to evaluate the effectiveness of 14 sessions of G-CBT for BD patients, comparing this intervention plus pharmacotherapy to treatment as usual (TAU; only pharmacotherapy). Forty-one patients with BD I and II participated in this study and were randomly allocated to each group (G-CBT: N = 27; TAU: N = 14). Thirty-seven participants completed the treatment (women: N = 66.67%; mean age = 41.5 years). QoL and mood symptoms were assessed in all participants. Scores changed significantly by the end of treatment in favor of the G-CBT group. The G-CBT group presented significantly better QoL in seven of the eight sub-items assessed with the Medical Outcomes Survey SF-36 scale. At the end of treatment, the G-CBT group exhibited lower scores for mania (not statistically significant) and depression (statistically significant) as well as a reduction in the frequency and duration of mood episodes (P < 0.01). The group variable was significant for the reduction of depression scores over time. This clinical change may explain the improvement in six of the eight subscales of QoL (P < 0.05). The G-CBT group showed better QoL in absolute values in all aspects and significant improvements in nearly all subscales. These results were not observed in the TAU control group.     

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.     

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.     

Memory mood congruency phenomenon in bipolar I disorder and major depression disorder patients

The objective of the present study was to evaluate memory performance in tasks with and without affective content (to confirm the mood congruency phenomenon) in acutely admitted patients with bipolar I disorder (BD) and major depression disorder (MDD) and in healthy participants. Seventy-eight participants (24 BD, 29 MDD, and 25 healthy controls) were evaluated. Three word lists were used as the memory task with affective content (positive, negative and indifferent). Psychiatric symptoms were also evaluated with rating scales (Young Mania Rating Scale for mania and Hamilton Depression Rating Scale for depression). Patients were selected during the first week of hospitalization. BD patients showed higher scores in the word span with positive tone than MDD patients and healthy controls (P = 0.002). No other difference was observed for tests with affective tone. MDD patients presented significantly lower scores in the Mini-Mental State Exam, logical memory test, visual recognition span, and digit span, while BD patients presented lower scores in the visual recognition test and digit span. Mood congruency effect was found for word span with positive tone among BD patients but no similar effect was observed among MDD patients for negative items. MDD patients presented more memory impairment than BD patients, but BD patients also showed memory impairment.     

Self-reported creativity in bipolar disorder: prevalence,types and associated outcomes in mania versus hypomania

Background

Bipolar (BP) disorder has been linked to creativity following investigation of prominent artists and controlled trials of creativity in BP disorder patients. However, it is unclear whether creativity is differentially expressed across the BP I and BP II subtypes.

Methods

219 patients (aged 19–63 years) diagnosed with BP disorder by clinical interview and DSM-IV criteria were asked whether they tended to be more creative during hypo/manic episodes, and answered five questions about personality styles associated with creativity. Qualitative analyses were performed on a smaller subset of 69 BP patients (n=19 BP I, n=50 BP II) who provided written responses of the types of creative activities engaged in when hypo/manic and any perceived advantages or disadvantages of their creative pursuits.

Results

82% of BP patients affirmed being creative when hypo/manic, with comparable results for the BP I and BP II subtypes (84% and 81% respectively). Both BP subtypes engaged mostly in writing, painting, work or business ideas and ‘other’ forms of art; however BP II patients were more likely to draw and be musical. Both subgroups reported the consequences of feeling good, being productive or quitting their project. BP I patients were more likely to overspend during their creative highs while BP II patients were more likely to experience improved focus and clarity. BP patients affirming creative highs were significantly more likely to report creative personality styles more generally outside of a mood episode.

Limitations

BP patients' self-reported creative activities were not retrospectively judged for quality or originality and so may reflect common creative abilities rather than exceptional quality. The impact of depressive episodes on creativity was not assessed. Uneven sample sizes in the BP I and BP II subgroups may have compromised statistical power.

Conclusion

Creativity during hypo/manic episodes was extremely common in both BP subtypes. While some nuances in activity type and outcomes were observed, no significant creative phenotype specific to BP I or BP II disorder emerged.     

Association between the so-called “activation syndrome” and bipolar II disorder,a related disorder,and bipolar suggestive features in outpatients with depression

Background

Activation syndrome (AS) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment. We aimed to clarify whether AS is associated with bipolar II disorder (BP-II) and its related disorder, i.e., bipolar disorder not otherwise specified (BP-NOS), which are often mistreated as major depressive disorder (MDD), as well as bipolar suggestive features in outpatients with depression.

Methods

The frequency of AS, bipolar suggestive features, and background variables in consecutive outpatients with a major depressive episode (MDE) due to BP-II/BP-NOS or MDD, who were naturalistically treated with antidepressants, were investigated and analyzed retrospectively.

Results

Of 157 evaluable patients (46 BP-II/BP-NOS, 111 MDD), 39 (24.8%) experienced AS. Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD (52.2% of BP-II/BP-NOS vs. 13.5% of MDD, p<0.01). Univariate analysis revealed that BP-II/BP-NOS diagnosis, cyclothymic temperament, early age at onset of first MDE, psychiatric comorbidities, and depressive mixed state (DMX) were significantly associated with AS development in the entire sample. Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS.

Limitations

This is a retrospective and naturalistic study; therefore, patient selection bias could have occurred.

Conclusions

Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS. Clinicians should re-evaluate underlying bipolarity when they confront AS. Antidepressants should be avoided for treating a current DMX beyond the unipolar–bipolar dichotomy. Prospective studies are needed to confirm these results.     

Affect recognition across manic and euthymic phases of bipolar disorder in Han-Chinese patients

Patients with bipolar disorder (BD) have affect recognition deficits. Whether affect recognition deficits constitute a state or trait marker of BD has great etiopathological significance. The current study aims to explore the interrelationships between affect recognition and basic neurocognitive functions for patients with BD across different mood states, using the Diagnostic Analysis of Non-Verbal Accuracy-2, Taiwanese version (DANVA-2-TW) as the index measure for affect recognition. To our knowledge, this is the first study examining affect recognition deficits of BPD across mood states in the Han Chinese population.     

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

Activation of the cardiac "sympathetic afferent" reflex (CSAR) has been reported to depress the arterial baroreflex and enhance the arterial chemoreflex via a central mechanism. In the present study, we used single-unit extracellular recording techniques to examine the effects of stimulation of cardiac sympathetic afferents on baro- or chemosensitive neurons in the nucleus tractus solitarius (NTS) in anesthetized rats. Of 54 barosensitive NTS neurons tested for their response to epicardial application of capsaicin (0.4 microg), 38 were significantly (P<0.01) inhibited by 38% while 16 did not respond. Of 42 NTS chemosensitive neurons tested for their response to capsaicin, 33 were significantly (P<0.01) excited by 47% while 9 did not respond. In addition, of 12 both barosensitive and chemosensitive NTS neurons tested for capsaicin, 2 were excited, 7 were inhibited, and 3 did not respond. In conclusion, this study indicates that CSAR activation inhibited NTS barosensitive neurons and excited NTS chemosensitive neurons, suggesting that the NTS plays an important role in processing the interactions between these cardiovascular reflexes.     

Specific alterations in plasma proteins during depressed,manic, and euthymic states of bipolar disorder

Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes.     

Iowa gambling task performance in euthymic bipolar I disorder: A meta-analysis and empirical study

Background

The Iowa Gambling Task (IGT) has been recommended as an index of reward sensitivity, which is elevated in bipolar disorder. We conducted a meta-analysis of IGT performance in euthymic bipolar I disorder compared with control participants. Findings indicated that people with bipolar disorder make more risky choices than control participants, though the effect is small (g=0.35). It is not clear which of the many processes involved in IGT performance are involved in producing the observed group difference.

Methods

Fifty-five euthymic people with bipolar disorder and 39 control participants completed the IGT. The Expectancy Valence Model was used to examine differences in IGT. We also examined whether variation in IGT performance within the bipolar group was related to current mood, illness course, impulsivity, or demographics.

Results

Bipolar and control groups did not differ on the total number of risky choices, rate of learning, or any of the parameters of the Expectancy Valence Model. IGT performance in bipolar disorder was not related to any of the examined individual differences.

Limitations

It is possible that there are group differences that are too small to detect at our sample size or that are not amenable to study via the Expectancy Valence Model.

Conclusions

We were unable to identify group differences on the IGT or correlates of IGT performance within bipolar disorder. Though the IGT may serve as a useful model for decision-making, its structure may make it unsuitable for behavioral assessment of reward sensitivity independent of punishment sensitivity.     

Aripiprazole monotherapy in the treatment of bipolar disorder: a meta-analysis

Introduction

Aripiprazole is approved for the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder. The aim of the present work was to review and meta-analyze the findings of all the available randomized double-blind controlled trials (RCTs) on the efficacy of aripiprazole in the treatment of bipolar disorder.

Material and methods

Aripiprazole RCTs were identified with a systematic search of MEDLINE and repositories. Standard meta-analytic techniques were applied.

Results

Two thousand three hundred and three patients took part in the aripiprazole acute mania RCTs. At week 3 the pooled aripiprazole vs. placebo effect size was 0.34 and the NNT was 6 for response and 14 for remission. On average, response started at day 3. Suicide rates were negligible for all groups in mania but they were not reported in the acute depression trials. The meta-analysis of acute bipolar depression RCTs revealed a significant difference at week 8 with a weak effect size equal to 0.17. The analysis of maintenance data suggest that the median survival time for the aripiprazole group was not evaluable (very long), while the median survival time for placebo was 118-203 days depending on the clinical subpopulation.

Discussion

The current meta-analysis supports the usefulness of aripiprazole during all phases of bipolar illness. Its effect against acute bipolar depression is weak and the efficacy during the maintenance phase is proven only against new manic episodes in patients with an index manic episode who had previously responded to aripiprazole during the acute phase.     

Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects

Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.     

Treatment adherence in bipolar I and schizoaffective disorder,bipolar type

Background

Poor adherence rates in Bipolar Disorder type I (BDI) and Schizoaffective Disorder, bipolar type (SAD) may be high This study was aimed at comparing the clinical correlates of adherence to treatment and the course of illness in BDI and SAD patients.

Methods

75 SAD and 150 BDI DSM-IV outpatients were included. Adherence was assessed on the basis of patients’ and care-givers’ reports and serum levels, when available. Socio-demographic, clinical and treatment variables were collected and compared between diagnostic subsamples and then between goodly and poorly adherent patients. Multiple logistic regressions were performed, controlling for diagnostic subsample differences, to identify correlates of adherence in BDI and SAD groups.

Results

Poor adherence was highly prevalent both in BDI (32%) and in SAD patients (44%), with no significant differences between diagnostic categories. Presence of psychotic symptoms (p=0.029), higher number of manic relapses (p<0.001), comorbidity with personality disorders (p=0.002), and lithium therapy (p=0.003) were associated with poor adherence to treatment. Diagnostic subgroup analyses showed different predictive models, with the BDI poorly adherent subsample being more likely to include comorbid personality and manic recurrences and the SAD poorly adherent subsample being less clinically predictable.

Limitations

The cross-sectional nature of the study limits de capacity to ascertain the direction of the relationship between certain variables.

Conclusions

Rates of poor adherence to oral treatments are similar in SAD and BDI. BDI patients with comorbid personality and substance use disorders are likely to be poorly adherent. Treatment adherence may be more difficult to predict in SAD patients.     

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n = 27), typical (n = 14), and other atypical antipsychotics (n = 19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p < 0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.