Management of cognitive impairment in bipolar disorder: a systematic review of randomized controlled trials.

Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis.

BACKGROUND: Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes. METHODS: Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2-6 days, 7-20 days, 21-28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine. RESULTS: The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591-1.903, p < 0.01). At 2-6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: -0.308-2.206, p = 0.139). At 7-20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499-1.538, p < 0.01). At 21-28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368-0.898, p < 0.01). LIMITATIONS: Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery. CONCLUSIONS: The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.

The effectiveness of repeated intravenous ketamine on depressive symptoms, suicidal ideation and functional disability in adults with major depressive disorder and bipolar disorder: Results from the Canadian Rapid Treatment Center of Excellence.

BACKGROUND: The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic. METHODS: Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168). RESULTS: Significant improvement in total depressive symptoms severity (p < 0.0001) was observed after four infusions of IV ketamine 0.5-0.75 mg/kg. Moreover, the response rate (QIDS-SR16 total score change ≥ 50%) was 27% and remission (QIDS-SR16 total score ≤5) rate was 13%. Patients receiving IV ketamine exhibited anxiolytic effects (p < 0.0001,), improved overall psychosocial function (p < 0.0001), and reduced suicidal ideation (p < 0.0001). Compared to the baseline infusion, dissociation severity significantly reduced in subsequent infusions. LIMITATIONS: This was a naturalistic, retrospective study, without a control group. CONCLUSIONS: IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD.