Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Are comorbid anxiety disorders a risk factor for suicide attempts in patients with mood disorders? A two-year prospective study.

BACKGROUND: Comorbid anxiety disorders have been considered a risk factor for suicidal behavior in patients with mood disorders, although results are controversial. The aim of this two-year prospective study was to determine if lifetime and current comorbid anxiety disorders at baseline were risk factors for suicide attempts during the two-year follow-up. METHODS: We evaluated 667 patients with mood disorders (504 with major depression and 167 with bipolar disorder) divided in two groups: those with lifetime comorbid anxiety disorders (n=229) and those without (n=438). Assessments were performed at baseline and at 3, 12, and 24 months. Kaplan-Meier survival analysis and log-rank test were used to evaluate the relationship between anxiety disorders and suicide attempts. Cox proportional hazard regression was performed to investigate clinical and demographic variables that were associated with suicide attempts during follow-up. RESULTS: Of the initial sample of 667 patients, 480 had all three follow-up interviews. During the follow-up, 63 patients (13.1%) attempted suicide at least once. There was no significant difference in survival curves for patients with and without comorbid anxiety disorders (log-rank test=0.269; P=0.604). Female gender (HR=3.66, P=0.001), previous suicide attempts (HR=3.27, P=0.001) and higher scores in the Buss-Durkee Hostility Inventory (HR=1.05, P≤0.001) were associated with future suicide attempts. CONCLUSIONS: Our results suggest that comorbid anxiety disorders were not risk factors for suicide attempts. Further studies were needed to determine the role of anxiety disorders as risk factors for suicide attempts.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Increased illness burden in women with comorbid bipolar and premenstrual dysphoric disorder: data from 1 099 women from STEP-BD study.

BACKGROUND: The impact of comorbid premenstrual dysphoric disorder (PMDD) in women with bipolar disorder (BD) is largely unknown. AIMS: We compared illness characteristics and female-specific mental health problems between women with BD with and without PMDD. MATERIALS & METHODS: A total of 1 099 women with BD who participated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were studied. Psychiatric diagnoses and illness characteristics were assessed using the Mini International Neuropsychiatric Interview. Female-specific mental health was assessed using a self-report questionnaire developed for STEP-BD. PMDD diagnosis was based on DSM-5 criteria. RESULTS: Women with comorbid BD and PMDD had an earlier onset of bipolar illness (P < 0.001) and higher rates of rapid cycling (P = 0.039), and increased number of past-year hypo/manic (P = 0.003), and lifetime/past-year depressive episodes (P < 0.05). Comorbid PMDD was also associated with higher proportion of panic disorder, post-traumatic stress disorder, generalized anxiety disorder, bulimia nervosa, substance abuse, and adult attention deficit disorder (all P < 0.05). There was a closer gap between BD onset and age of menarche in women with comorbid PMDD (P = 0.003). Women with comorbid PMDD reported more severe mood symptoms during the perinatal period and while taking oral contraceptives (P < 0.001). DISCUSSION: The results from this study is consistent with research suggesting that sensitivity to endogenous hormones may impact the onset and the clinical course of BD. CONCLUSIONS: The comorbidity between PMDD and BD is associated with worse clinical outcomes and increased illness burden.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3 T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Brazilian psychiatric brain bank: a new contribution tool to network studies.

There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group (Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20 months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2 ± 9.0 years. The average postmortem interval was 16 h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.

Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia.

Although the neurobiological basis of bipolar disorder (BD) remains unknown, mitochondrial dysfunction, oxidative stress and oxidative cell damage have been identified in this disease. Uncoupling proteins (UCP) are proton carriers located in the inner membrane of the mitochondria involved in controlling the production of mitochondrial reactive oxygen species (ROS). Therefore, in this study we wished to investigate the involvement of UCP in BD. We analyzed the RNA and protein levels of UCP2 in the dorsolateral prefrontal cortex (DLPFC) of subjects with BD and schizophrenia (SCZ) and assessed the potential relationship between the antioxidant superoxide dismutase (SOD1 and SOD2) and UCP2 in the same region. Our results showed a downregulation of UCP2 mRNA levels in the DLPFC of subjects with BD and SCZ. There were no differences in UCP2 protein, SOD1 and SOD2 levels between patients and controls. Although more studies are necessary, our results suggest that UCP2 is not been used as a compensatory mechanism to oppose the higher levels of oxidative stress found in BD and SCZ.

Childhood maltreatment and clinical outcomes of bipolar disorder.

OBJECTIVE: Adverse life events, especially early trauma, play a major role in the course and expression of bipolar disorder (BD). The aim of this article is to present a systematic review about the impact of childhood trauma on the clinical course of BD. METHOD: A computer-aided search was performed in Medline, ISI database, EMBASE, PsychInfo, Centre for Reviews and Dissemination, and Databases of Thomson Reuters at April 2011, supplemented by works identified from the reference lists of the first selected papers. Two investigators systematically and independently examined all articles, selecting those according inclusion and exclusion criteria. RESULTS: Four hundred fifteen articles were identified, of which 19 remained in the review after exclusion criteria were applied. In general, childhood maltreatment predicted worsening clinical course of BD. After assessing the quality of the data and of the measurements, childhood maltreatment can be strongly associated to early onset of disorder, suicidality, and substance abuse disorder in patients with BD. CONCLUSION: Data suggest that childhood abuse and neglect are risk factors associated with worsening clinical course of BD. The conclusions should be interpreted with caution because all the studies included are cross-sectional and the majority are showing inconsistencies regarding childhood trauma as independent variable and how it is assessed.

A randomized controlled trial of cognitive behavioral group therapy for bipolar disorder.

BACKGROUND: This study evaluated the effectiveness of adjunctive cognitive behavioral group therapy (CBGT) to prevent recurrence of episodes in euthymic patients with bipolar disorder. METHODS: A randomized controlled single-blind trial was conducted with 50 patients with bipolar disorder types I and II followed up for at least 12 months in an outpatient service and whose disease was in remission. An experimental CBGT manual was developed and added to treatment as usual (TAU), and results were compared with TAU alone. RESULTS: Intention-to-treat analysis showed that there was no difference between groups in terms of time until any relapse (Wilcoxon = 0.667; p = 0.414). When considering type of relapse, there was still no difference in either depressive (Wilcoxon = 3.328; p = 0.068) or manic episodes (Wilcoxon = 1.498; p = 0.221). Although occurrence of episodes also did not differ between groups (χ(2) = 0.28; p = 0.59), median time to relapse was longer for patients treated with CBGT compared to TAU (Mann-Whitney = -2.554; p = 0.011). CONCLUSIONS: Time to recurrence and number of episodes were not different in the group of patients treated with CBGT. However, median time to relapse was shorter in the TAU group. Studies with larger samples may help to clarify whether our CBGT approach prevents new episodes of bipolar disorder. Our findings also indicated that CBGT is feasible in euthymic patients with bipolar disorder and should be investigated in future studies. To our knowledge, this is the first publication of a controlled trial of CBGT for euthymic patients with bipolar disorder.

Therapeutic potential of interleukin-6 antagonism in bipolar disorder.

Bipolar disorder (BD) is a chronic, severe, and highly disabling psychiatric disorder. Its underlying neurobiology remains largely unclear. A significant body of evidence indicates that inflammatory activation expressed by increased cytokines is relevant in its pathophysiology. IL-6 is one of the most important cytokines involved in the pathogenesis of immune and inflammatory disorders. Several studies recently showed increased levels of IL-6 in manic and depressive episodes and also during euthymia in subjects with BD. Tocilizumab is an IL-6 receptor antagonist being marketed for the treatment of rheumatoid arthritis and Castleman's disease. In this article we discuss the possibility that tocilizumab may have a therapeutic role in treatment of BD through its anti-inflammatory action.

Treatment emergent affective switch: a controlled study.

OBJECTIVE: To study the clinical features of treatment emergent affective switch (TEAS) in comparison with spontaneous mania. METHODS: Twelve patients with TEAS within a 12-week period (average) of starting standard antidepressant medication were compared with 12 patients with spontaneous mania. RESULTS: Patients with TEAS were older, had longer duration of illness, more previous episodes, higher prevalence of subclinical hypothyroidism, and reported more previous episodes of mania associated with antidepressant use. TEAS was less severe, with a lower incidence of psychotic symptoms, lower Young Mania Rating Scale index score and rarely required hospitalization. The interval from intervention to response and remission was similar in both groups. CONCLUSION: TEAS was less severe, but had similar duration when compared with spontaneous mania. These results cannot directly answer the question of whether there is a causal relationship between antidepressant use and TEAS. While it is also possible that patients with longer duration of illness and higher cycle frequencies are more likely to experience episodes, it is difficult to attribute lesser severity of TEAS episodes to these clinical factors. Our observations are consistent with the suggestion that patients with longer duration of illness and previous history of TEAS may be at a greater risk of switching to mania during the use of antidepressants.

Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study.

BACKGROUND: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. METHODS: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. RESULTS: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. CONCLUSIONS: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.

Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia.

The purpose of this study was to compare the efficacy and tolerability of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia. This was an 8-week, multicentre, randomized, double-blind, parallel-group comparison of venlafaxine and amitriptyline. Outpatients with DSM-IV major depression, a minimum score of 20 on the 21-item Hamilton Depression Rating Scale (HAM-D), and depressive symptoms for at least 1 month were eligible. Patients were randomly assigned to venlafaxine or amitriptyline, both drugs titrated to a maximum of 150 mg/day until study day 15. The primary efficacy variables were the final on-therapy scores on the HAM-D, Montgomery-Asberg Depression Rating Scale and Clinical Global Impression severity scales. Data were evaluated on an intent-to-treat basis using the LOCF method. One hundred and 16 patients were randomized, and 115 were evaluated for efficacy. Both drugs showed efficacy in the treatment of depression with or without melancholia. No significant differences were noted between treatments for any efficacy parameter. However, significantly (p < 0.05) more patients in the amitriptyline group had at least one adverse event. These results should support the efficacy and tolerability of venlafaxine in comparison with amitriptyline for treating major depression with or without melancholia.

Analysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia.

It has been suggested that the serotonin transporter (5-hydroxytryptamine-transporter or 5-HTT) may be involved in the pathogenesis of affective disorders. Recently, Collier et al. (1996) found that the frequency of the low-activity short variant (s) of the 5-HTT-linked polymorphic region (5-HTTLPR) was higher among patients with affective disorders than in normal controls. However, since the observed level of significance was not high, they suggest that these findings should be replicated in independent samples. We have analyzed 86 unrelated patients (47 with bipolar disorder and 39 with schizophrenia) and 98 normal controls from the Brazilian population for the 5-HTTLPR. Statistical analysis revealed that the genotypes (LL, Ls, ss) as well as the estimated allele frequencies (L,s) did not differ significantly among the three studied groups or between bipolar and normal controls. In addition, although not statistically significant, the genotype ss in our sample was less frequent among our bipolar patients than in our normal controls (12.8% versus 16.3%) which is the opposite of what was found by Collier et al. (24% versus 18%) in the European study. Although it will be important to extend the present analysis in a larger sample, our preliminary results suggest that the 5-HTTLPR does not seem to play a major role in the genetics of bipolar and schizophrenic disorders at least in this group of Brazilian psychiatric patients.

A quantitative magnetic resonance imaging study of caudate and lenticular nucleus gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity.

The authors investigated whether there were differences in caudate and lenticular nucleus volumes in depressed patients relative to comparison subjects, and whether differences in basal ganglia volume were associated with treatment response to fluoxetine. Brain magnetic resonance images were obtained from 38 unipolar depressed patients and 20 matched comparison subjects. Patients were divided into groups of 'responders' and 'non-responders' based on change in the 17-item Hamilton Depression Rating Scale (HDRS) score after a 10-week open trial of fluoxetine, 20 mg/day. There were no group mean differences in caudate and lenticular nucleus volumes between patients and comparison subjects. Female treatment responders tended to have larger caudate nucleus volumes than male 'responders', and also larger right caudate nucleus volumes than their female 'non-responder' counterparts. Baseline HDRS scores correlated negatively with left caudate nucleus volume in depressed patients. Thus, in mild to moderately depressed patients, we were unable to find differences in caudate and lenticular nucleus-gray matter volumes relative to comparison subjects. One possible reason is that caudate nucleus-gray matter volume and severity of depression are inversely correlated, suggesting that severity of depression may be an important covariate when comparing caudate volumes in depressed patients and control subjects.