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.

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.

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.

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.

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.

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.

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.

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.

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.

The influence of DST and TRH test administration on depression assessments: a controlled study.

Significant antidepressant effects have been reported after administration of dexamethasone and thyrotropin-releasing hormone (TRH). The purpose of this study was to evaluate whether or not the administration of the dexamethasone suppression test (DST) and TRH test in depressed patients, just before their entering clinical trials, has any impact on their symptoms. The Hamilton Rating Scale for Depression was administered to 166 subjects at screen visit, 1 week later (baseline visit), and 1 week after beginning treatment with fluoxetine 20 mg/day (week-1). Between screen and baseline visits, 62 patients were administered the DST alone, 6 underwent the TRH test alone, and 26 received both the DST and the TRH test. Seventy-two patients were not administered either test. No statistically significant differences in depression scores were found at screen, baseline and week-1 visits between patients who underwent neuroendocrine tests and those who did not. Our data suggest that the administration of neuroendocrine tests such as the DST and the TRH test does not have a statistically significant effect on depressive symptoms and, therefore, does not interfere with study results and interpretation.

Influence of phototherapy treatment duration for seasonal affective disorder: outcome at one vs. two weeks.

Most previous phototherapy research has been conducted on trials of 1 week duration. This study compares response to phototherapy at weeks 1 and 2. All subjects (n = 26) were between 18 and 65 years and met Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised, (DSM III-R) criteria for major depression, recurrent, seasonal pattern and had a Hamilton Depression Rating Scale score (HAM-D) > or = 20. A rater blinded to treatment schedule and study hypothesis repeated the HAM-D-31 1 and 2 weeks after baseline to assess treatment response to bright light. Response rates at week 1 defined by 50% reduction in HAM-D-31 and HAM-D-31 score < 8 were 62% and 27%, respectively. At week 2, however, 65% had a 50% reduction in HAM-D-31 and 62% had a HAM-D-31 < score 8 (chi-square = 6, p = 0.01). Four patients (15%) who were nonresponders at week 1 responded after 2 weeks. The results show a statistically different outcome after 2 weeks of treatment and suggest the necessity of longer trials of phototherapy.

Changes in regional cerebral blood flow following light treatment for seasonal affective disorder: responders versus nonresponders.

BACKGROUND: Several brain imaging studies of antidepressant pharmacologic treatment utilizing single photon emission computed tomography (SPECT) have reported a normalization of deficits in cerebral blood flow (CBF) associated with recovery; other studies report no change, or a reduction in CBF following successful treatment. There have been no published SPECT studies of seasonal affective disorder (SAD) assessing response to light treatment in relation to changes in regional CBF (rCBF). In this study, we sought to test the hypothesis that increases in rCBF would be observed in SAD patients who responded to light treatment. METHODS: Ten depressed patients with SAD underwent functional brain imaging studies with 99mTc-hexamethylpropyleneamine oxime SPECT before and after light treatment. RESULTS: Relative increases in rCBF were observed in all brain regions compared to cerebellum in treatment responders, whereas nonresponders showed no change or decreases in rCBF relative to cerebellum. Significant differences in mean percentage change in rCBF between responders (n = 5) and nonresponders (n = 5) were detected in frontal and cingulate cortex, and thalamus. CONCLUSIONS: These findings provide preliminary support for the hypothesis that an increase in rCBF is associated with recovery from depression in SAD.

Variability of brain lithium levels during maintenance treatment: a magnetic resonance spectroscopy study.

In vivo magnetic resonance spectroscopy (MRS) was used to determine the relationship between serum and brain lithium levels in bipolar patients (n=25). Over the broad range of serum lithium levels observed, the correlation (r=.68) with brain lithium levels was high. This correlation was much weaker (r=.39) when limited to only those patients with serum lithium levels in the range of 0.6-1.0 mmol/l. This variability may account for failure of lithium prophylaxis in some patients who have serum lithium levels in the therapeutic range.

The human brain resonance of choline-containing compounds is similar in patients receiving lithium treatment and controls: an in vivo proton magnetic resonance spectroscopy study.

Lithium specifically and potentially inhibits membrane transport of choline. However, the effect of lithium on human neuronal choline content is unknown. This study was performed to determine if lithium alters the human brain choline concentration in vivo. In vivo proton magnetic resonance spectroscopy was used to compare the relative brain concentration of choline-containing compounds in seven lithium-treated patients and six lithium-free controls. No significant difference was observed in the mean relative choline resonance between the patient and control groups. Lithium treatment did not appear to alter the overall brain content of choline-containing compounds. It remains possible that a component of these compounds, particularly free choline, is elevated during lithium treatment.

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

The authors investigated whether there were differences in cerebral and cerebellar gray and white matter volumes in depressed patients compared to controls, and whether this was associated with treatment response to fluoxetine. Brain magnetic resonance images were obtained from 38 unipolar depressed patients and 20 age, gender, and educationally matched comparison subjects. Patients were divided into groups of "responders" and "nonresponders" based on change in 17-item Hamilton Depression Rating Scale (HDRS) after an 8-week standardized trial of fluoxetine, 20 mg/day. There were no group mean differences in cerebral or cerebellar tissue volumes between patients and controls, or responders and nonresponders. For nonresponders to fluoxetine treatment, cerebral and cerebellar gray matter volume, and total cerebellar tissue volume decreased as baseline HDRS increased. The results suggest an association between gray matter volume and severity of illness in nonresponders to fluoxetine treatment.

Choline in the treatment of rapid-cycling bipolar disorder: clinical and neurochemical findings in lithium-treated patients.

This study examined choline augmentation of lithium for rapid-cycling bipolar disorder. Choline bitartrate was given openly to 6 consecutive lithium-treated outpatients with rapid-cycling bipolar disorder. Five patients also underwent brain proton magnetic resonance spectroscopy. Five of 6 rapid-cycling patients had a substantial reduction in manic symptoms, and 4 patients had a marked reduction in all mood symptoms during choline therapy. The patients who responded to choline all exhibited a substantial rise in the basal ganglia concentration of choline-containing compounds. Choline was well tolerated in all cases. Choline, in the presence of lithium, was a safe and effective treatment for 4 of 6 rapid-cycling patients in our series. A hypothesis is suggested to explain both lithium refractoriness in patients with bipolar disorder and the action of choline in mania, which involves the interaction between phosphatidylinositol and phosphatidylcholine second-messenger systems.

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.