Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Brain age and cognitive functioning in first-episode bipolar disorder.

BACKGROUND: There is significant heterogeneity in cognitive function in patients with bipolar I disorder (BDI); however, there is a dearth of research into biological mechanisms that might underlie cognitive heterogeneity, especially at disease onset. To this end, this study investigated the association between accelerated or delayed age-related brain structural changes and cognition in early-stage BDI. METHODS: First episode patients with BDI (n = 80) underwent cognitive assessment to yield demographically normed composite global and domain-specific scores in verbal memory, non-verbal memory, working memory, processing speed, attention, and executive functioning. Structural magnetic resonance imaging data were also collected from all participants and subjected to machine learning to compute the brain-predicted age difference (brainPAD), calculated by subtracting chronological age from age predicted by neuroimaging data (positive brainPAD values indicating age-related acceleration in brain structural changes and negative values indicating delay). Patients were divided into tertiles based on brainPAD values, and cognitive performance compared amongst tertiles with ANCOVA. RESULTS: Patients in the lowest (delayed) tertile of brainPAD values (brainPAD range -17.9 to -6.5 years) had significantly lower global cognitive scores (p = 0.025) compared to patients in the age-congruent tertile (brainPAD range -5.3 to 2.4 yrs), and significantly lower verbal memory scores (p = 0.001) compared to the age-congruent and accelerated (brainPAD range 2.8 to 16.1 yrs) tertiles. CONCLUSION: These results provide evidence linking cognitive dysfunction in the early stage of BDI to apparent delay in typical age-related brain changes. Further studies are required to assess how age-related brain changes and cognitive functioning evolve over time.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Subjective cognitive functioning, depressive symptoms, and objective cognitive functioning in people with treatment-resistant psychosis.

Introduction: Relationships between subjective cognitive functioning (SCF), objective cognitive functioning (OCF), and depressive symptoms are poorly understood in treatment-resistant psychosis (TRP). This study (a) compares SCF in TRP using positively and negatively worded scales, (b) assess these scales' accuracy, and (c) explores the association between these scales and depressive symptoms. We hypothesised that both SCF scales would be highly correlated, minimally associated with OCF, and similarly associated with depressive symptoms. Methods: Archival clinical data from 52 TRP inpatients was utilised. OCF composite scores were derived from a broad neuropsychological battery. SCF was assessed using the norm-referenced PROMIS 2.0 Cognitive Abilities (positively worded) and Concerns (negatively worded) subscales. A depressive symptom score was derived from the Positive and Negative Syndrome Scale. Results: SCF ratings were higher in patients than OCF. There was a small but significant correlation between PROMIS subscales (r = .30). Neither PROMIS subscale was associated with OCF (r = -.11, r = .01). Depressive symptoms were correlated with the positively (r = -.29) but not negatively worded scale (r = -.13). Conclusion: Individuals with TRP inaccurately rate their cognitive functioning and tend to overestimate their ability. Positively and negatively worded SCF scales associate variably with depressive symptoms, indicating they may not be used interchangeably in TRP.

Criterion validity of the brief test of adult cognition by telephone (BTACT) for mild traumatic brain injury.

OBJECTIVES: There is a growing demand for remote assessment options for measuring cognition after mild traumatic brain injury (mTBI). The current study evaluated the criterion validity of the Brief Test of Adult Cognition by Telephone (BTACT) in distinguishing between adults with mTBI and trauma controls (TC) who sustained injuries not involving the head or neck. METHODS: The BTACT was administered to the mTBI (n = 46) and TC (n = 35) groups at 1-2 weeks post-injury. Participants also completed the Rivermead Post Concussion Symptoms Questionnaire. RESULTS: The BTACT global composite score did not significantly differ between the groups (t(79) = -1.04, p = 0.30); the effect size was small (d = 0.23). In receiver operating characteristic curve analyses, the BTACT demonstrated poor accuracy in differentiating between the groups (AUC = 0.567, SE = 0.065, 95% CI [0.44, 0.69]). The BTACT's ability to discriminate between mTBI and TCs did not improve after excluding mTBI participants (n = 15) who denied ongoing cognitive symptoms (AUC = 0.567, SE = 0.072, 95% CI [0.43, 0.71]). CONCLUSIONS: The BTACT may lack sensitivity to subacute cognitive impairment attributable to mTBI (i.e., not explained by bodily pain, post-traumatic stress, and other nonspecific effects of injury).

Repetitive Transcranial Magnetic Stimulation Shows Longitudinal Improvements in Memory in Patients With Treatment-Resistant Depression.

BACKGROUND: Cognitive dysfunction (CD) is a commonly reported symptom of major depressive disorder (MDD). Patients with treatment-resistant depression (TRD) tend to experience greater rates of CD; however, treatment options are limited. Repetitive transcranial magnetic stimulation (rTMS) is effective in treating affective symptoms in patients with TRD, but its potential effect on CD in TRD has not been established. OBJECTIVES: This study sought to establish the potential cognitive benefits of rTMS in patients with TRD. MATERIALS AND METHODS: This study used data from a noninferiority clinical trial investigating two excitatory rTMS protocols to the left dorsolateral prefrontal cortex in unipolar outpatients with TRD. Cognitive testing was performed at baseline and three months posttreatment in 47 patients and a demographically matched cohort of 22 healthy volunteers. Changes in cognitive performance from baseline to posttreatment were assessed using repeated-measures analysis of variance, using both normative and individualized cognitive scoring methods. RESULTS: Patients with baseline neurocognitive dysfunction showed significant changes in verbal memory at three months posttreatment when using individualized cognitive scoring. Furthermore, improvement in verbal memory within this subset was associated with improvements in affective symptoms. LIMITATIONS: This analysis was performed on a relatively small sample of patients with TRD who were not prescreened for CD and did not include a clinical comparator group. CONCLUSIONS: rTMS may be associated with improvements in verbal memory in patients with TRD who present with global CD and who are clinical responders to the treatment. These findings warrant replication in a larger sample as well as further investigations into the neural mechanisms of cognitive improvement after rTMS.

Weight gain as a risk factor for progressive neurochemical abnormalities in first episode mania patients: a longitudinal magnetic resonance spectroscopy study.

BACKGROUND: We previously reported that bipolar disorder (BD) patients with clinically significant weight gain (CSWG; ⩾7% of baseline weight) in the 12 months after their first manic episode experienced greater limbic brain volume loss than patients without CSWG. It is unknown whether CSWG is also a risk factor for progressive neurochemical abnormalities. METHODS: We investigated whether 12-month CSWG predicted greater 12-month decreases in hippocampal N-acetylaspartate (NAA) and greater increases in glutamate + glutamine (Glx) following a first manic episode. In BD patients (n = 58) and healthy comparator subjects (HS; n = 34), we measured baseline and 12-month hippocampal NAA and Glx using bilateral 3-Tesla single-voxel proton magnetic resonance spectroscopy. We used general linear models for repeated measures to investigate whether CSWG predicted neurochemical changes. RESULTS: Thirty-three percent of patients and 18% of HS experienced CSWG. After correcting for multiple comparisons, CSWG in patients predicted a greater decrease in left hippocampal NAA (effect size = -0.52, p = 0.005). CSWG also predicted a greater decrease in left hippocampal NAA in HS with a similar effect size (-0.53). A model including patients and HS found an effect of CSWG on Δleft NAA (p = 0.007), but no diagnosis effect and no diagnosis × CSWG interaction, confirming that CSWG had similar effects in patients and HS. CONCLUSION: CSWG is a risk factor for decreasing hippocampal NAA in BD patients and HS. These results suggest that the well-known finding of reduced NAA in BD may result from higher body mass index in patients rather than BD diagnosis.

Cognitive subgroups in first episode bipolar I disorder: Relation to clinical and brain volumetric variables.

OBJECTIVE: Distinct cognitive subgroups are seen in patients with long duration bipolar I disorder (BDI), possibly reflective of underlying pathophysiological differences. It is unknown whether such cognitive heterogeneity is present at illness onset. We applied latent class analysis (LCA) to cognitive test scores in first episode BDI patients. Exploratory analysis elucidated whether impaired subgroups were characterized by 'early neurodevelopmental' (low premorbid IQ and intracranial volume) versus 'later neurodevelopmental' (decline from premorbid to current IQ, changes in relative grey (GM)/white (WM) matter volumes) pathology. METHODS: Recently recovered first manic episode BDI patients (n = 91) and healthy controls (HC, n = 63) comprised the study sample. LCA identified subgroups based on processing speed, verbal memory, non-verbal memory, executive functioning, attention and working memory scores. Subgroups were compared amongst each other and HC on premorbid/current IQ, intracranial (ICV), total brain and regional volumes. RESULTS: Three cognitive subgroups emerged: (i) globally impaired (GI, n = 31), scoring 0.5-1 SD below demographically corrected norms across domains, (ii) selectively impaired (SI, n = 47), with predominant processing speed deficits and (iii) high performing (HP, n = 13), with above-average cognitive performance. GI patients showed a 'later neurodevelopmental' pattern, with normal ICV, significant decline from premorbid to current IQ, higher total GM and lower total WM (with respect to total brain volume) versus SI and HC (p = 0.003). GI patients had higher left frontal pole GM versus HC (p < 0.05, FWE corrected). CONCLUSIONS: A globally impaired patient subgroup is identifiable in first episode BDI, possibly characterized by unique neurodevelopmental pathologic processes proximal to illness onset.

Assessment of Prorated Scoring of an Abbreviated Protocol for the National Institutes of Health Toolbox Cognition Battery.

OBJECTIVE: To evaluate an abbreviated NIH Toolbox Cognition Battery (NIHTB-CB) protocol that can be administered remotely without any in-person assessments, and explore the agreement between prorated scores from the abbreviated protocol and standard scores from the full protocol. METHODS: Participant-level age-corrected NIHTB-CB data were extracted from six studies in individuals with a history of stroke, mild traumatic brain injury (mTBI), treatment-resistant psychosis, and healthy controls, with testing administered under standard conditions. Prorated fluid and total cognition scores were estimated using regression equations that excluded the three fluid cognition NIHTB-CB instruments which cannot be administered remotely. Paired t tests and intraclass correlations (ICCs) were used to compare the standard and prorated scores. RESULTS: Data were available for 245 participants. For fluid cognition, overall prorated scores were higher than standard scores (mean difference = +4.5, SD = 14.3; p < 0.001; ICC = 0.86). For total cognition, overall prorated scores were higher than standard scores (mean difference = +2.7, SD = 8.3; p < 0.001; ICC = 0.88). These differences were significant in the stroke and mTBI groups, but not in the healthy control or psychosis groups. CONCLUSIONS: Prorated scores from an abbreviated NIHTB-CB protocol are not a valid replacement for the scores from the standard protocol. Alternative approaches to administering the full protocol, or corrections to scoring of the abbreviated protocol, require further study and validation.

Weight gain as a predictor of frontal and temporal lobe volume loss in bipolar disorder: A prospective MRI study.

OBJECTIVES: A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining ≥7% of baseline weight) over 12 months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. METHODS: In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. RESULTS: After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d] = -1.01, P = 0.002), left cingulate gyrus (ES = -1.31, P < 0.001), and left middle temporal gyrus (ES = -0.96, P = 0.004). Middle temporal volume loss predicted more days with depression (ß = -0.406, P = 0.010). CONCLUSIONS: These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment.

Affective cognition in bipolar disorder: A systematic review by the ISBD targeting cognition task force.

BACKGROUND: Impairments in affective cognition are part of the neurocognitive profile and possible treatment targets in bipolar disorder (BD), but the findings are heterogeneous. The International Society of Bipolar Disorder (ISBD) Targeting Cognition Task Force conducted a systematic review to (i) identify the most consistent findings in affective cognition in BD, and (ii) provide suggestions for affective cognitive domains for future study and meta-analyses. METHODS: The review included original studies reporting behavioral measures of affective cognition in BD patients vs controls following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement. Searches were conducted on PubMed/MEDLINE, EMBASE, and PsychInfo from inception until November 2018. RESULTS: A total of 106 articles were included (of which nine included data for several affective domains); 41 studies assessed emotional face processing; 23 studies investigated reactivity to emotional words and images; 3 investigated explicit emotion regulation; 17 assessed implicit emotion regulation; 31 assessed reward processing and affective decision making. In general, findings were inconsistent. The most consistent findings were trait-related difficulties in facial emotion recognition and implicit emotion regulation, and impairments in reward processing and affective decision making during mood episodes. Studies using eye-tracking and facial emotion analysis revealed subtle trait-related abnormalities in emotional reactivity. CONCLUSION: The ISBD Task Force recommends facial expression recognition, implicit emotion regulation, and reward processing as domains for future research and meta-analyses. An important step to aid comparability between studies in the field would be to reach consensus on an affective cognition test battery for BD.

Relationship between body mass index and hippocampal glutamate/glutamine in bipolar disorder.

BACKGROUND: We previously reported that patients with early-stage bipolar disorder, but not healthy comparison controls, had body mass index (BMI)-related volume reductions in limbic brain areas, suggesting that the structural brain changes characteristic of bipolar disorder were more pronounced with increased weight. AIMS: To determine whether the most consistently reported neurochemical abnormality in bipolar disorder, increased glutamate/glutamine (Glx), was also more prominent with higher BMI. METHOD: We used single-voxel proton magnetic resonance spectroscopy to measure hippocampal Glx in 51 patients with first-episode mania (mean BMI = 24.1) and 28 healthy controls (mean BMI = 23.3). RESULTS: In patients, but not healthy controls, linear regression demonstrated that higher BMI predicted greater Glx. Factorial ANCOVA showed a significant BMI × diagnosis interaction, confirming a distinct effect of weight on Glx in patients. CONCLUSIONS: Together with our volumetric studies, these results suggest that higher BMI is associated with more pronounced structural and neurochemical limbic brain changes in bipolar disorder, even in early-stage patients with low obesity rates.

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.

Response inhibition and interference control in patients with bipolar I disorder and first-degree relatives.

OBJECTIVES: The current study aimed to assess both response inhibition (RI) and interference control (IC) in euthymic patients with bipolar disorder (BD-Ps) as well as asymptomatic first-degree relatives (BD-Rs) and healthy controls (HCs) in order to evaluate trait-as opposed to illness-associated features of these components. METHODS: BD-Ps (n = 35) who had been in the euthymic state for at least six months, BD-Rs (n = 30), and HCs (n = 33) completed a Stop-Signal Task (SST) and Stroop Task to assess RI and IC, respectively. Groups were compared on the stop-signal reaction time (SSRT), stop-signal delay (SSD), mean reaction time on go trials (go-RT), Stroop interference score (S-interference), and number of errors on the color-word-naming trial (S-error). Associations between the patient's clinical features and RI and IC, between the patient's treatment and RI and IC, and between RI and IC in each group were investigated. RESULTS: BD-Ps and BD-Rs had significantly shorter go-RT and SSD, and longer SSRT compared to HCs, with these scores being similar between the BD-Ps and BD-Rs. Also, both BD-Ps and BD-Rs made significantly more S-errors than HCs, whereas, the S-interference score was not significantly different between groups. There were no significant correlations between Stroop Task and SST scores within each group, nor between clinical features or treatment variables and RI and IC in BD-Ps. CONCLUSIONS: Overall, impairment in RI and IC (only on S-error score) was present in both patients and relatives. The persistence of these deficits in the absence of mood symptoms suggests that these features may represent candidate endophenotypes for bipolar disorder.

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.

12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder.

OBJECTIVES: Although cognitive deficits are observed in the early stages of bipolar disorder, the longitudinal course of neuropsychological functioning during this period is unknown. Such knowledge could provide etiologic clues into the cognitive deficits associated with the illness, and could inform early treatment interventions. The purpose of the present study was to evaluate cognitive change in bipolar disorder in the first year after the initial manic episode. METHODS: From an initial pool of 65 newly diagnosed patients with bipolar disorder (within three months of the end of the first manic or mixed episode) and 36 demographically similar healthy participants, 42 patients [mean age 22.9 years, standard deviation (SD) = 4.0] and 23 healthy participants [mean age 22.9 years (SD = 4.9)] completed baseline, six-month, and one-year neuropsychological assessments of multiple domains including processing speed, attention, verbal and nonverbal memory, working memory, and executive function. Patients also received clinical assessments, including mood ratings. RESULTS: Although patients showed consistently poorer cognitive performance than healthy individuals in most cognitive domains, patients showed a linear improvement over time in processing speed (p = 0.008) and executive function (p = 0.004) relative to the comparison group. Among patients, those without a history of alcohol/substance abuse or who were taken off an antipsychotic treatment during the study showed better improvement. CONCLUSIONS: The early course of cognitive functioning in bipolar disorder is likely influenced by multiple factors. Nevertheless, patients with bipolar disorder showed select cognitive improvements in the first year after resolution of their initial manic episode. Several clinical variables were associated with better recovery, including absence of substance abuse and discontinuation of antipsychotic treatment during the study. These and other factors require further investigation to better understand their contributions to longitudinal cognitive functioning in early bipolar disorder.

Long-term neuropsychological safety of subgenual cingulate gyrus deep brain stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) is a promising investigational intervention for treatment-resistant depression (TRD), but long-term outcome data are limited. Serial neuropsychological evaluations, using a comprehensive battery, were conducted on four subjects with TRD prior to surgery, and up to 42 months post-operatively. Reliable change methodology suggested general stability and/or select statistically reliable improvement in cognitive abilities over time. This is the first known set of multi-year neuropsychological follow-up data for SCG DBS for TRD. Observed improvements are likely attributable to reduced depressive symptomatology, recovery of functional capacities, and/or specific practice effects of repeated assessment.

The relationship between clinical outcomes and quality of life in first-episode mania: a longitudinal analysis.

OBJECTIVES: Despite growing attention to the relationship between bipolar disorder (BD) and quality of life (QoL), there remains a lack of information about QoL in the early stages of BD, and about the course of QoL in people with BD over time. Here, we report on QoL and symptomatic outcomes over a 1.5-year period in a Canadian sample of first-episode mania patients. METHODS: Patients (n = 63) with DSM-IV-TR BD type I recovering from a recent episode of mania were recruited from a university-based hospital setting in Vancouver, BC, Canada and assessed at six monthly intervals for 18 months. In addition to symptomatic and cognitive assessments, two self-report QoL scales [the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Medical Outcomes Study Short Form 36 (SF-36)] were administered. RESULTS: Baseline QoL scores were high, with mean Q-LES-Q scores at 70% of the maximum possible score; QoL continued to show a trend towards improvement over time. Multiple hierarchical regressions were used to explore predictors of QoL over time, finding that: (i) length of illness and severity of depressive symptoms at baseline predicted Q-LES-Q scores at both baseline and six months; (ii) the number of previous depressive episodes and severity of depression at baseline and 12 months all predicted QoL at 12 months; and (iii) only severity of depressive symptoms at 12 months predicted QoL at 18 months. CONCLUSIONS: Our observation that QoL in patients who have recently experienced an episode of mania can be relatively preserved offers hope, both for healthcare providers and for those newly diagnosed. Further, that severity of depressive symptoms even in the early stages of the disease was the consistent predictor of QoL suggests that depressive symptoms need to be aggressively treated to improve QoL.