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.     

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.     

Neurological soft signs in bipolar I disorder patients

Background: Neurological soft signs (NSS) have been reported to be more prevalent in patients with schizophrenia compared to other psychiatric and non-psychiatric controls. However, this issue in bipolar I disorder seems to be understudied. Aims: The aims of the study were to examine the extent to which NSS are associated with bipolar I disorder cases compared to healthy controls, to assess the possible relationship between NSS and clinical dimensions of the disorder, and to explore the association of sociodemographic characteristics with the occurrence of NSS in cases with this disorder. Methods: Predominantly treatment naïve cases of bipolar I disorder from rural communities were assessed for NSS using the Neurological Evaluation Scale (NES). Results: This study showed that patients with bipolar I disorder performed significantly worse on two NES items from the sensory integration subscale, on one item from motor coordination and on four items from the ‘others’ subscale, the highest difference in performance being in items under the sequencing of complex motor acts subscale. Clinical dimensions and sociodemographic characteristics appeared to have no relationship with NES total score. Conclusions: Bipolar I disorder patients seem to have more neurological dysfunction compared to healthy controls particularly in the area of sequencing of complex motor acts. In addition, the finding suggests that NSS in bipolar I disorder are stable neurological abnormalities established at its onset or may be essential characteristic features of the disorder representing stable disease process that existed long before its onset.     

Structure-function associations in hippocampus in bipolar disorder

Hippocampus volume decreases and verbal memory deficits have been reported in bipolar disorder (BD) as independent observations. We investigated potential associations between these deficits in subjects with BD. Hippocampus volumes were measured on magnetic resonance images of 31 subjects with BD and 32 healthy comparison (HC) subjects. The California Verbal Learning Test-Second Edition (CVLT) assessed verbal memory function in these subjects. Compared to the HC group, the BD group showed both significantly smaller hippocampus volumes and impaired performance on CVLT tests of immediate, short delay and long delay cued and free recall. Further, smaller hippocampus volume correlated with impaired performance in BD. Post hoc analyses revealed a trend towards improved memory in BD subjects taking antidepressant medications. These results support associations between morphological changes in hippocampus structure in BD and verbal memory impairment. They provide preliminary evidence pharmacotherapy may reverse hippocampus-related memory deficits.     

Cognitive functions and cognitive styles in young euthymic patients with bipolar I disorder

Background

Recent evidences suggest that bipolar disorder patients do not return to premorbid functioning levels during the inter-episode periods. Cognitive deficits may impair patients working and functioning status and may also have negative impact on other aspects of thinking.

Objectives

To assess the prevalence of cognitive dysfunction in patients with bipolar disorder in euthymic state and to explore any evident cognitive style problems.

Method

Case-control naturalistic study 60 patients with bipolar I disorder in euthymic state according to DSM-IV were recruited and subdivided into two groups each contains of 30 patients; (Group BPM) euthymic patients with recent manic episode, and Group BPD euthymic patients with recent depressive episode. Both groups were further compared with control group (Group C) consisted of 30 frequency matched healthy volunteers. Groups were subjected to the following: 1-clinical psychiatric examination, 2-Hamilton Depression Scale (HAMD-17) and Bech–Rafaelsen Melancholia Scale (MES) for patients’ group (BPD), 3-Young Mania Rating Scale (YMRS) and Bech–Rafaelsen Mania Scale (MAS) for patients’ group (BPM), 4-assessment of euthymic state of mood included both MAS and MES, 5-MMSE, MTS and CDT were performed to assess cognitive functions, 6-cognitive styles evaluation included Fear of Failure, Hopelessness Scale, (the Social Dysfunction and Aggression Scale SDAS-9 and Arabic Anger Scale.

Results

Definite cognitive function impairment and different patterns of cognitive style were detected in case groups. MMSE, MTS and CDT scores were statistically significant. Fear of Failure Scale Scores were higher in BPM; 16 (53.33%) reported severe intensity compared to 16 (53.33%) of BPD Group reporting moderate intensity and 30 (100%) of the control group reporting only mild intensity of fear of failure with statistically significant differences. Although patients were in euthymic state; Hopelessness Scale discriminated between those with affective disorders and controls and other scores for hostility SADS-9 and Arabic Anger Scale. Moreover, measures of cognitive styles showed differences among patients of the case groups who joined psychotherapy program in their management (28) compared to those who did not (32).

Limitation

Cognitive impact of psychotropic drugs could not be eliminated since the current study is naturalistic study.

Conclusions

Those with BAD in euthymic state suffer from cognitive dysfunction and some aspects of cognitive styles that may negatively interfere with their performance. Psychotherapeutic programs should consider these findings in their approaches for better impact on patients’ quality of life and overall treatment outcome.     

Differences in functional connectivity in major depression versus bipolar II depression

Background

Objective methods of differentiating unipolar versus bipolar depression would enhance our ability to treat these disorders by providing more accurate diagnoses. One first step towards developing diagnostic methodology is determining whether brain function as assessed by functional MRI (fMRI) and functional connectivity analyses might differentiate the two disorders.

Methods

Fourteen subjects with bipolar II depression and 26 subjects with recurrent unipolar depression were studied using fMRI and functional connectivity analyses.

Results

The first key finding of this study was that functional connectivity of the right posterior cingulate cortex differentiates bipolar II and unipolar depression. Additionally, results suggest that functional connectivity of this region is associated with suicidal ideation and depression severity in unipolar but not bipolar II depression.

Limitations

The primary limitation is the relatively small sample size, particularly for the correlational analyses.

Conclusions

The functional connectivity of right posterior cingulate cortex may differential unipolar from bipolar II depression. Further, connectivity of this region may be associated with depression severity and suicide risk in unipolar but not bipolar depression.     

Trait impulsivity in patients with mood disorders

BACKGROUND: Impulsivity is a key component of the manic behavior of bipolar disorder and is reported to occur in bipolar patients as a stable characteristic, i.e. a trait. Nevertheless, impulsivity has not been widely studied in depressed bipolar patients. We assessed impulsivity in depressed and euthymic bipolar and unipolar patients and healthy controls. We hypothesized that bipolar subjects would have higher levels of trait impulsivity than the comparison groups. METHODS: Twenty-four depressed bipolar, 24 depressed unipolar, 12 euthymic bipolar, and 10 euthymic unipolar patients, as well as 51 healthy subjects were evaluated with the Barratt Impulsiveness Scale (BIS). Analysis of covariance with age and sex as covariates was used to compare mean group differences. RESULTS: Depressed bipolar, euthymic bipolar, and depressed unipolar patients did not differ, and showed greater impulsivity than healthy controls on all of the BIS scales. Euthymic unipolar patients scored higher than healthy controls only on motor impulsivity. LIMITATIONS: Higher number of past substance abusers in the bipolar groups, and no control for anxiety and personality disorders, as well as small sample sizes, limit the reach of this study. CONCLUSIONS: This study replicates prior findings of stable trait impulsivity in bipolar disorder patients, and extends them, confirming that this trait can be demonstrated in depressed patients, as well as manic and euthymic ones. Trait impulsivity may be the result of repeated mood episodes or be present prior to their onset, either way it would influence the clinical presentation of bipolar disorder.     

Behavioral Activation System (BAS) differences in bipolar I and II disorder

Background

A growing body of evidence supports the Behavioral Activation System (BAS) dyresgulation model of bipolar disorder, however its application to bipolar II disorder is limited. The current study examines its potential relevance to bipolar I and II disorders. We specifically sought to determine whether bipolar sub-types would differ in terms of BAS sensitivity, and examined for differential prospective relationships between BAS sensitivity and bipolar I and II symptom expression.

Method

Participants were recruited from the Sydney-based Black Dog Institute. Diagnostic groups were derived on the basis of agreement between clinician and DSM-IV diagnoses from structured interviews. Baseline measures of BAS sensitivity, mood symptoms and anxiety were completed. Self-rated mood was assessed over a 6-month period. Clinician-rated mood status was re-assessed at follow-up to determine the predictive utility of BAS scores.

Results

The sample comprised 151 bipolar participants (69 bipolar I, 82 bipolar II). BAS-Drive and Reward Responsiveness scores were significantly higher in bipolar I disorder participants. BAS sub-scale scores were uniquely positively associated with mood variability in bipolar I and II disorder. BAS-Drive and Reward Responsiveness scores were positively associated with bipolar I hypo(mania), and with the former also positively associated with bipolar II depression. BAS scores did not predict bipolar I or II mood episode status at 6-month follow-up.

Limitations

BAS sensitivity was self-reported; inability to establish independence of BAS scores from residual symptoms; lack of controlling for medication effects; inability to determine the influence of life events; length of follow-up period may have not been sufficient to evaluate the predictive utility of BAS sensitivity for mood episodes or detect course of illness differences across bipolar sub-types.

Conclusions

Differences in BAS sensitivity and associations with mood variability were quantified in bipolar I and II disorder, suggesting the need for tailored treatments for these separate conditions. Further investigation of the role of the BAS in bipolar sub-types is warranted.     

Neural recruitment during failed motor inhibition differentiates youths with bipolar disorder and severe mood dysregulation

Controversy exists about whether non-episodic irritability (operationalized as severe mood dysregulation, SMD) should be considered a developmental presentation of pediatric bipolar disorder (BD). While assessments of brain function may address this controversy, only one fMRI study has compared BD versus SMD. We compared neural activation in BD, SMD, and controls during a motor inhibition task, since motor disinhibition is an important clinical feature in both BD and SMD. During failed inhibition, BD youths exhibited less activation in the right anterior cingulate cortex (ACC) and right nucleus accumbens relative to both SMD and healthy youths. Exploratory analyses indicate that, in BD youths, reduced activation in the right ACC may be independent of comorbid ADHD. These findings highlight neural distinctions between the phenotypically related BD and SMD populations.     

Low baseline startle and deficient affective startle modulation in remitted bipolar disorder patients and their unaffected siblings

We examined whether startle abnormalities are present in bipolar disorder (BD) patients and their unaffected siblings. Twenty‐one remitted patients with BD, 19 unaffected siblings, and 42 controls were presented with 18 pleasant, 18 unpleasant, and 18 neutral pictures. Acoustic probes (104 dB) were presented during 12 of 18 pictures in each affective category at 300, 3000, and 4500 ms after picture onset, so that there were 4 pictures per valence per probe onset type. Baseline startle was assessed during blank screens and was found reduced in patients and sibling groups. We found startle inhibition with the 300 probes and a linear increase in amplitude with valence with the late probes in controls; these effects were absent in patients and their siblings. Low startle and blunted startle reactivity may represent trait deficits in remitted BD patients and their relatives, possibly associated with attentional deficits and adaptive down‐regulation of emotion.     

Increased risk of developing stroke among patients with bipolar disorder after an acute mood episode: a six-year follow-up study

BACKGROUND: Despite cerebrovascular diseases having been reported as one of the major causes of death among patients with bipolar disorder, there is scant information on the risk of stroke among this patient population. This study estimated the relative risk of developing stroke among patients with bipolar disorder in 6 years following hospitalization for an acute mood episode compared with patients undergoing appendectomy. METHODS: Two study cohorts were identified from the Taiwan National Health Insurance Research Database for the year 1998: patients hospitalized with bipolar disorder, and patients undergoing an appendectomy. Follow-up was undertaken to determine whether sampled patients had utilized emergency medical services for the management of any type of stroke in the period 1998-2003. RESULTS: Stroke occurred among 2.97% of patients with bipolar disorder and 1.50% of patients undergoing appendectomy between 1998 and 2003. The adjusted odds ratio of developing stroke, by cohort, shows that after adjusting for demographic characteristics, comorbid medical disorder, and substance or alcohol dependence, patients with bipolar disorder were more likely to develop stroke (OR=2.05; 95% CI=1.73-3.54). LIMITATIONS: The validity of diagnoses, lacking of information on smoking, body mass index, and socioeconomic status, and possible selection bias might compromise the findings. CONCLUSIONS: During the six-year follow-up period, the likelihood of developing stroke was twice as great amongst patients with bipolar disorder as patients undergoing an appendectomy. A requirement exists for the initiation of research providing an understanding of the pathophysiological mechanisms of the association between stroke and bipolar disorder.     

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.     

Risks associated with gender differences in bipolar I disorder

Background

Previous studies have demonstrated that bipolar patients may differ in several features according to gender, but a number of the differences found remain controversial.

Methods

The demographic, illness course, clinical, comorbidity and temperament characteristics of a total of 1090 consecutive DSM-IV bipolar I manic inpatients were compared according to gender.

Results

Bipolar illness in women was characterised by the predominance of depression, as indicated by a depressive polarity at onset, higher rates of mixed mania, more suicidal behaviour, and a greater number of temperaments with depressive propensities. In contrast, the manic component was found to predominate in men. Men also had an earlier onset of their illness. Women displayed more comorbidities with eating, anxiety, and endocrine/metabolic disorders, whereas men were more comorbid with alcoholism and other forms of substance abuse, neurological, and cancer disorders. The following independent variables were associated with male gender: being single (+), depressive temperament (−), excessive alcohol use (+), cyclothymic temperament (−), excessive other substance use (+), mood congruent psychotic features (+), and manic polarity at onset (+).

Limitations

The retrospective design and the sample being potentially not representative of the bipolar disorder population are limitations.

Conclusions

Findings from this study tend to confirm most of the differences previously observed among bipolar men and women. Furthermore, these results draw attention to the risks that may be specifically linked to gender differences in bipolar I patients.     

Regional brain gray matter abnormalities in patients with bipolar II disorder: A comparison study with bipolar I patients and healthy controls

Despite the high prevalence and clinical significance of bipolar II disorder (BD II), the underlying pathophysiology is not well explored in previous studies. The purpose of the current study was to investigate brain gray matter abnormalities in BD II. High resolution magnetic resonance brain images from 23 BD II patients, 23 sex- and age-matched patients with bipolar I disorder (BD I) and 23 healthy controls were acquired and processed according to the optimized voxel-based morphometry protocol. The processed gray matter tissue volumes were compared among the three groups. Both the BD II and BD I group showed gray matter deficits in the ventromedial prefrontal regions, compared to controls. The BD I group had widespread gray matter reductions in the bilateral frontal, temporal, parietal and parahippocampal cortices, compared to controls. However, gray matter reductions in these regions were not found in the BD II group. With a less conservative statistical threshold, the BD II group showed additional gray matter deficits in the anterior limbic cortices. Our data suggest that gray matter deficits in the ventromedial prefrontal and anterior limbic cortices are common in both BD II and BD I. On the other hand, different pattern of gray matter abnormalities between BD II and BD I found in this study supports that two subtypes may have different neurobiological characteristics.     

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.     

A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment

In order to assess the association between therapeutic response to lithium treatment and fronto-limbic brain structures’ volumes in bipolar I patients (BPI) 24 BPI and 11 healthy comparisons underwent MRI scans at baseline and 4 weeks later. The BPIs received lithium during the 4 week period with a goal of achieving therapeutic blood levels of >0.5 mEq/L (mean level 0.67 mEq/L). Mood symptoms were rated with the Hamilton Depression and the Young Mania Rating Scales at baseline and after 4 weeks, and response was defined as >50% decrease on either scale. Hippocampus, amygdala, prefrontal (PFC), dorsolateral prefrontal (DLPFC), and anterior cingulate cortex (ACC) volumes were obtained by Freesurfer image analysis suite. According to baseline symptoms and treatment response, patients were assigned to three groups: euthymics (n=6), responders (n=12) and non-responders (n=6). Taken over both time periods, non-responders had smaller right amygdala than healthy comparisons and euthymic BPI (p=0.035 and p=0.003, respectively). When baseline and after treatment volumes were compared, there was a significant enlargement in left PFC and left DLPFC in BPI who responded to treatment (p=0.002 and p=0.006, respectively). Left hippocampus and right ACC volumes decreased in non-responders (p=0.02 and p=0.0001, respectively). According to the findings decreased left hippocampus and right ACC volumes may be markers of non-response to lithium amongst BPI. Smaller right amygdala may reflect symptomatic remission and be a marker of treatment non-response. Increases in left PFC and left DLPFC as a result of lithium treatment may relate to lithium's neurotrophic effects.     

Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder

BACKGROUND: We sought to determine the prevalence of, and association between, reproductive cycle-associated mood symptoms in women with affective disorders. We hypothesized that symptoms would correlate with each other across a woman's reproductive life span in both major depression (MDD) and bipolar I disorder (BP). METHODS: 2412 women with, MDD or BP were asked standardized questions about mood symptoms prior to menstruation, within a month of childbirth and during perimenopause. Lifetime rates for each of these symptom types were determined and an odds ratio was calculated correlating each of the types with the others. RESULTS: Of 2524 women with mood disorders, 67.7% reported premenstrual symptoms. Of those at risk, 20.9% reported postpartum symptoms and 26.4% reported perimenopausal symptoms. The rates did not differ between women with MDD and BP but were significantly different from women who were never ill. The symptoms were significantly correlated in women with MDD with odds ratios from 1.66 to 1.82, but were not in women with BP. LIMITATIONS: This is a secondary analysis of a sample that was collected for other purposes and is based upon retrospective reporting. CONCLUSIONS: Reproductive cycle-associated mood symptoms were commonly reported in women with mood disorders and did not differ based on diagnosis. In MDD, but not BP, the occurrence of these symptoms was trait-like as the presence of one predicted the occurrence of the others. Further prospective study is required to clarify the determinants of this trait.     

Reduced expression of glyoxalase-1 mRNA in mood disorder patients

Glyoxalase-1 (Glo1) is an antioxidant enzyme which detoxifies alpha-ketoaldehydes to prevent the accumulation of pro-oxidant compounds, such as methylglyoxal, in all cell types. Glo1 has been suggested to be involved in anxiety disorders, autism, and Alzheimer's disease. Mood disorders have a high rate of comorbidity with anxiety disorders although, to date, little is known of the involvement of Glo1 in the pathophysiology of these conditions. In the present study, we examined the expression levels of Glo1 mRNA in peripheral white blood cells of mood disorder patients to understand the role of Glo1 in mood disorders. Quantitative real-time polymerase chain reaction experiments revealed that reduced expression of Glo1 mRNA was observed in major depressive and bipolar disorder patients in a current depressive state, as compared with healthy control subjects. In contrast, the expression of Glo1 mRNA in major depressive and bipolar patients, in a remissive state, showed no significant alteration when compared with healthy control subjects. These results suggest that the aberrant expression of Glo1 might be involved in the pathophysiology of mood disorders.