Use of a point-of-care web-based application to enhance adherence to the CANMAT and ISBD 2018 guidelines for the management of bipolar disorder.

OBJECTIVES: While clinical guidelines exist for the management of bipolar disorder (BD), there are significant challenges to their widespread dissemination and implementation in clinical practice. The Canadian Network of Mood and Anxiety Treatment Improving Patient Care and Outcomes in the Treatment of Bipolar Disorder (C-IMPACT BD) web-based application was developed for use at the point-of-care to improve adherence to guidelines for evidence-based pharmacological management of BD. METHODS: C-IMPACT BD uses a point-of-care practice assessment which, via adaptive questioning of patient-specific information, text/video descriptions of the guidelines, and pop-up prompts delivers personalized, evidence-based treatment recommendations for patients with BD. In order to inform quality improvement of the newly developed tool, a sample of Canadian physicians were invited to use the application and record its influence on their prescribing behavior. RESULTS: Of 375 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder for whom a point-of-care practice assessment was completed, a change in therapy was considered for 225 (60.0%). Prior to completing the assessment, 59.6% of these patients were receiving first-line therapy recommended for their phase of illness. Following the assessment, the overall number of patients for whom a first-line recommended therapy was being considered increased significantly to 76.9% (p = 0.0001). CONCLUSIONS: Outcomes suggest that the C-IMPACT BD web-based application has the potential to improve physician adherence to clinical treatment guidelines. Formal research investigations are warranted to explore the impact of this tool on physician prescribing behavior and patient outcomes.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

OBJECTIVES: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided-a critical gap which the current update aims to address. METHOD: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. RESULTS: No agents met threshold for first-line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second-line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second-line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first-line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second-line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first-line, and lithium and olanzapine identified as second-line options. CONCLUSION: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Hippocampal neurochemical markers in bipolar disorder patients following the first-manic episode: A prospective 12-month proton magnetic resonance spectroscopy study.

OBJECTIVE: Previous studies reported decreased N-acetyl aspartate and increased Glx (the sum of glutamate plus glutamine) in bipolar disorder. Since these studies included patients at different stages of illness, it is unknown whether these changes have a causal role or a consequence of multiple episodes and treatments. The studies in early-stage bipolar disorder patients have the potential to provide answers to these issues. Therefore, we evaluated N-acetyl aspartate and Glx levels in hippocampi of first-episode bipolar disorder patients and health subjects at baseline and at 12 months, and examined the impact of episode recurrence on these measures. METHOD: We used single-voxel proton magnetic resonance spectroscopy to compare the hippocampal neurometabolites ( N-acetyl aspartate and Glx) levels between 41 patients with bipolar disorder following recovery from their first-manic episode and 27 matched healthy subjects at recruitment and 12 months later. We also compared N-acetyl aspartate and Glx levels between patients who had a recurrence of a mood episode and those who did not. RESULTS: There was no main effect of either group (diagnosis) or time for hippocampal N-acetyl aspartate and Glx levels in bipolar disorder patients and healthy subjects. We also did not find any group-by-time interaction for the levels of these metabolites. There were also no differences in N-acetyl aspartate and Glx between patients who experienced a recurrence of a mood episode and those who did not over 12-month follow-up. CONCLUSION: Our data suggest that N-acetyl aspartate and Glx levels are not altered in early stage bipolar disorder. Further, these data suggest that episode recurrence in early stages does not have a significant impact on the levels of these metabolites. These may suggest that there may be an early window for intervention to potentially arrest neuroprogression of the disease.

Neuroprogression and episode recurrence in bipolar I disorder: A study of gray matter volume changes in first-episode mania and association with clinical outcome.

OBJECTIVES: Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. METHODS: A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr ), and patients in sustained remission (BDwell ). RESULTS: The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. CONCLUSIONS: GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal.

Impact of depressive episodes on cognitive deficits in early bipolar disorder: data from the Systematic Treatment Optimization Programme for Early Mania (STOP-EM).

BACKGROUND: Although manic episodes reportedly contribute to cognitive deficits in bipolar I disorder, the contribution of depressive episodes is poorly researched. AIMS: We investigated the impact of depressive episodes on cognitive function early in the course of bipolar I disorder. METHOD: A total of 68 patients and 38 controls from the Systematic Treatment Optimization Programme for Early Mania (STOP-EM) first-episode mania programme were examined. We conducted (a) a cross-sectional analysis of the impact of prior depressive episodes on baseline cognitive function and (b) a prospective analysis assessing the contribution of depression recurrence within 1 year following a first episode of mania on cognitive functioning. RESULTS: The cross-sectional analysis showed no significant differences between patients with past depressive episodes compared with those without, on overall or individual domains of cognitive function (all P>0.09). The prospective analysis failed to reveal a significant group×time interaction for cognitive decline from baseline to 1 year (P = 0.99) in patients with a recurrence of depressive episodes compared with those with no recurrence. However, impaired verbal memory at baseline was associated with a depression recurrence within 1 year. CONCLUSIONS: Although deficits in all domains of cognitive function are seen in patients early in the course of bipolar disorder, depressive episodes do not confer additional burden on cognitive function. However, poorer verbal memory may serve as a marker for increased susceptibility to depression recurrence early in the course of illness.

Relationship between frontostriatal morphology and executive function deficits in bipolar I disorder following a first manic episode: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

OBJECTIVES: Executive function impairments are a core feature of bipolar I disorder (BD-I), not only present during acute episodes but also persisting following remission of mood symptoms. Despite advances in knowledge regarding the neural basis of executive functions in healthy subjects, research into morphological abnormalities underlying the deficits in BD-I is lacking. METHODS: Patients with BD-I within three months of sustained remission from their first manic episode (n = 41) underwent neuropsychological testing and a 3T magnetic resonance imaging scan and were compared to healthy subjects matched for age, sex, and premorbid IQ (n = 30). Group dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) and caudate volumes were examined and analyzed for relationships with the average score from three computerized tests of executive function: Spatial Working Memory, Stockings of Cambridge, and Intradimensional/Extradimensional Shift. RESULTS: Right caudate volumes were enlarged in patients (z = 3.57, p < 0.05 corrected). No differences in DLPFC volumes were found. Patients showed large deficits in executive function relative to healthy subjects (d = -0.92, p < 0.001). While in healthy subjects, a larger right (r = +0.39, p < 0.05) and left (r = +0.44, p < 0.05) caudate was associated with better executive function score, in patients, larger right (r = -0.36, p < 0.05) and left (r = -0.34, p < 0.05) volumes correlated with poorer performance. CONCLUSIONS: Although the etiology of gray matter changes is unknown, volume increases in the right caudate may be an important factor underlying executive function impairments during remission in patients with BD-I.

Real-world Evidence for Impact of Opioid Agonist Therapy on Nonfatal Overdose in Patients with Opioid Use Disorder during the COVID-19 Pandemic.

OBJECTIVES: The primary objectives of this study were to describe the demographics and clinical characteristics of patients who were treated with buprenorphine extended-release versus buprenorphine-naloxone sublingual tablets versus methadone in a real-world setting and to evaluate the difference in nonfatal overdose events between treatment cohorts. METHODS: This study was a retrospective chart review of patients with opioid use disorder initiating opioid agonist therapy in Canada during the outset of the COVID-19 pandemic (March 11, 2020 to October 31, 2021). Three treatment cohorts were defined by the initial prescribed opioid agonist therapy regimen: buprenorphine extended-release, buprenorphine-naloxone sublingual tablets, and methadone. Baseline characteristics, as well as treatment status, overdose events, and substance use 6 months after treatment initiation were collected using a standardized form. RESULTS: Nine clinics provided data on 379 patient cases. The incidence rate (number of events per 100 person-years) for a self-reported nonfatal overdose was 46.8 (n = 18), 19.3 (n = 10), and 1.7 (n = 1) in the methadone, buprenorphine-naloxone sublingual tablets, and buprenorphine extended-release cohorts, respectively. The risk-adjusted difference for the proportion of patients with nonfatal overdose was 8.59% (95% confidence interval, 3.10-14.08%; P = 0.0022) for methadone versus buprenorphine extended-release and 6.51% (95% confidence interval, 1.46-11.56%; P = 0.0115) for buprenorphine-naloxone sublingual tablets versus buprenorphine extended-release. CONCLUSIONS: Buprenorphine extended-release was associated with lower rates of nonfatal overdose events compared with daily opioid agonist therapy. Given the limitations of this naturalistic, retrospective design, further prospective studies are needed to validate these findings and demonstrate the potential for long-acting opioid agonist therapy in addressing the opioid crisis.

A Longitudinal Study of the Relationships Between Mood Symptoms, Body Mass Index, and Serum Adipokines in Bipolar Disorder.

OBJECTIVE: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. METHODS: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSM-IV-defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. RESULTS: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (ß = -0.385, P = .04) and adipsin (ß = -0.376, P = .03) levels and higher lipocalin-2 levels (ß = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (ß = 0.482, P < .01). Furthermore, lower adiponectin (ß = -0.353, P = .01) and leptin (ß = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (ß = 0.496, P < .01) and leptin (ß = 0.421, P < .01) levels predicted BMI gain. CONCLUSIONS: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules.

Metacognitive knowledge and experience in recently diagnosed patients with bipolar disorder.

INTRODUCTION: Metacognition, which refers to an individual's ability to assess their own cognitive ability or performance, is poorly understood in bipolar disorder. This study was conducted to evaluate two aspects of metacognitive ability in recently diagnosed patients with bipolar disorder: (a) metacognitive knowledge, pertaining to awareness of one's own general cognitive functioning; and (b) metacognitive experience, referring to awareness of one's cognitive performance on a specific, online cognitive task. METHOD: Participants consisted of 50 clinically euthymic patients recently diagnosed with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) bipolar I disorder who were within three months of resolution of their first manic episode, and a comparison group of 38 demographically similar healthy volunteers. To assess metacognitive knowledge, participants provided a general rating of their estimated cognitive ability prior to completing a neuropsychological battery, and self-ratings were compared to actual ability based on a composite score of overall cognitive functioning. To assess metacognitive experience, subjects provided a postdiction rating of their perceived memory performance after completing a list learning verbal memory test, and self-ratings were compared to actual memory performance. Measures of both relative and absolute accuracy of ratings were obtained. RESULTS: Results indicated that patients showed diminished accuracy in rating their general cognitive ability, implying deficits in metacognitive knowledge. In contrast, patients were accurate in rating their online memory performance, suggesting intact metacognitive experience. CONCLUSIONS: Findings suggest that in patients with bipolar disorder, intact task-specific cognitive self-appraisals may fail to generalize to or to modify inaccurate global cognitive self-appraisals. Further research using more comprehensive metacognitive tasks is warranted in bipolar disorder.

Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder.

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse.

Are cognitive deficits similar in remitted early bipolar I disorder patients treated with lithium or valproate? Data from the STOP-EM study.

In bipolar disorder (BD), lithium and valproate are both reportedly associated with mild cognitive deficits with impaired psychomotor speed and verbal memory ascribed to both while impairments in learning and attention are mainly attributed to valproate. However, there are few direct comparisons of the impact of lithium and valproate on cognitive function in early BD. Using data from the STOP-EM study, we compared neurocognitive functioning in BD patients, who had recently recovered from a first episode of mania, and were on treatment with lithium (n = 34) or valproate (n = 38), to a comparable sample of healthy controls (HC; n = 40), on the domains of processing speed, attention, verbal memory, nonverbal memory, working memory and executive functions. The three groups were comparable on socio-demographic (all p > 0.12) and clinical variables (all p > 0.08). MANOVA revealed a significant difference between the three groups on overall cognitive functioning (Wilk's lambda = 0.644; F = 3.775; p < 0.001). On post-hoc Tukey test, the valproate group performed poorer on working memory compared to the lithium (p = 0.001) and HC groups (p < 0.001). There was no significant difference between the lithium and valproate groups on other cognitive domains (all p > 0.13). Treatment with valproate and not lithium may be associated with working memory deficits early in the course of BD.

Verbal memory impairment in new onset bipolar disorder: Relationship with frontal and medial temporal morphology.

OBJECTIVES: Verbal memory (VM) impairment is a trait feature of bipolar I disorder (BDI) that is present at illness onset and associated with functional outcome. However, little is known about the morphological abnormalities underlying this deficit early in the disease course. This study examined the neurobiological correlates of VM impairment in euthymic newly diagnosed patients, with attention to frontal and medial temporal (MT) structures known to contribute to VM. METHODS: Euthymic patients with BDI recently recovered from their first episode of mania (n = 42) were compared with healthy subjects (n = 37) using measures of the California Verbal Learning Test (CVLT-II) associated with frontal and MT functioning. A subset of participants had 3T MRI scan (n = 31 patient group, n = 30 healthy subject group). Hippocampal and prefrontal volumes were analyzed using FreeSurfer 5.1 and correlated with their corresponding CVLT-II subscores. RESULTS: Patients showed decreased performance in total learning as well as short and long delay verbal recall. Consistent with MT dysfunction, they also showed deficits in recognition discriminability and learning slope. In the patient group only, left hippocampal volumes were negatively correlated with these measures. CONCLUSIONS: These results suggest that anomalous MT functioning is involved with VM impairment early in the course of BDI.

Sex differences in cognitive functioning in patients with bipolar disorder who recently recovered from a first episode of mania: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

BACKGROUND: Studies investigating bipolar disorder (BD) showed that healthy patterns of sex differences in cognitive functioning are altered within this population, but is it unknown whether these alterations are present in BD patients early in their course of illness. METHODS: Patients with bipolar I disorder (36 males, 38 female), who had recently experienced their first manic or mixed episode were tested along with healthy controls (39 males, 59 females) similar in age, sex and premorbid IQ. Cognitive function was assessed through a comprehensive neuropsychological test battery. RESULTS: Significant group effects were found in a majority of administered tests (p<0.05) with patients performing worse than healthy controls. Significant sex effects (p<0.05) were observed on tasks of spatial working memory and sustained attention, with males performing better than females. No significant group by sex interaction was found in any of the tasks administered. LIMITATIONS: The cognitive battery employed in this study may not have been optimally sensitive in detecting sex differences. CONCLUSIONS: The results suggest that unlike patients with long standing multi-episode BD or schizophrenia, healthy cognitive sex differences are maintained in patients with early BD, following recovery from a first-episode of mania. These findings highlight the progressive nature of the illness and provide justification for an early intervention.

Cognitive change in the year after a first manic episode: association between clinical outcome and cognitive performance early in the course of bipolar I disorder.

OBJECTIVE: Cognitive impairments are present immediately following recovery from a first episode of mania, although at a lesser severity than those seen in more chronic patients with bipolar I disorder. Little is known about how deficits evolve over the course of illness, however, and whether these changes are associated with disease progression. METHOD: Patients with bipolar I disorder (DSM-IV-TR) receiving naturalistic clinical follow-up from the Systematic Treatment Optimization Program for Early Mania (STOP-EM) from July 2004 to May 2013 completed a comprehensive cognitive battery following recovery from their first manic episode and again 1 year later. Performance was compared between patients who experienced a recurrence of a mood episode (BDrecur) (n = 26) versus those that maintained remission (BDwell) (n = 27) over follow-up, as well as healthy comparison subjects (HS) (n = 31). RESULTS: While both BDrecur and BDwell had impairments in overall cognitive performance relative to HS at baseline (mean difference = -0.59, P < .001; mean difference = -0.43, P < .05, respectively), at follow-up BDrecur showed deficits compared to both HS (mean difference = -0.62, P = .001) and BDwell (mean difference = -0.41, P = .05), with BDwell cognition similar to that in HS (mean difference = -0.21, P > .4). BDwell showed larger improvements over follow-up relative to both other groups (P < .05). While changes in BDrecur did not differ from HS, in this group more days in a manic or hypomanic episode was associated with performance declines (r = -0.40, P < .05). CONCLUSIONS: While cognitive function improves in patients who sustain remission in the year following a first manic episode, those who experience a recurrence remain impaired, with performance declines being most apparent in those who experienced longer manic or hypomanic episodes.

Neurocognitive functioning in overweight and obese patients with bipolar disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

OBJECTIVE: Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode. METHOD: Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control. subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight-obese patients, and normal weight healthy control subjects. RESULTS: There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group. CONCLUSIONS: These data suggest that overweight-obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD.

Comparison of neuropsychological effects of adjunctive risperidone or quetiapine in euthymic patients with bipolar I disorder.

Although associations between antipsychotic use and neuropsychological impairment in bipolar I disorder have been observed, there is a lack of studies comparing the effects of specific agents used in this population. We compared performance between patients receiving maintenance treatment with mood stabilizer monotherapy (n=15), adjunctive risperidone (n=15) or quetiapine (n=17), and a group of demographically matched healthy controls (n=28) on tests of executive function (working memory, set shifting, and inhibition) and verbal learning. Despite having a similar clinical profile, patients being treated with risperidone showed significantly impaired working memory, set-shifting, and verbal learning (P<0.05) compared with those either on mood stabilizer monotherapy or adjunctive quetiapine. Although randomized controlled trials are required to confirm the cognitive side effects of medications prescribed for maintenance treatment of bipolar I disorder, preliminary results indicate that addition of risperidone to a mood stabilizer has a negative impact on executive function and verbal learning, an effect not shared with quetiapine.