Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).

We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.

Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.

Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.

We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

Ketamine, an N-methyl-d-aspartate receptor antagonist, has been “repurposed” as a rapid-acting antidepressant for treatment-resistant depression (TRD). The s-enantiomer of ketamine, “esketamine,” was FDA approved for TRD and depressive symptoms in adults with major depressive disorder with suicidal ideations/behaviors. Intravenous (IV) ketamine, although financially less expensive, is often not covered by insurance and intranasal (IN) esketamine, although covered by insurance can be expensive. There is a paucity of literature on efficacy data comparing subanesthetic IV ketamine and IN esketamine for TRD in a real-world scenario. Thus, we conducted this study comparing the efficacy and the number of treatments required to achieve remission/response with repeated use of subanesthetic IV ketamine/IN esketamine among TRD patients.

This was an observational study where we included adults (≥18 years) with TRD who provided consent and had received up to 6 IV ketamine infusions (0.5 mg/kg, infused over 40 minutes) or up to 8 intranasal (IN) esketamine (56/84 mg) treatments for TRD at the Mayo Clinic Depression Center. Depression symptoms were measured utilizing the self-report 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale before and 24 hours after ketamine/esketamine treatment. Remission and response were defined as QIDS-SR 16 score ≤5 and ≥50% change in QIDS-SR 16, respectively. Continuous variables are reported as means ± SD and categorical variables as counts and percentages. The Wilcoxon rank-sum test was used to compare continuous variables. Chi-square and Fisher’s exact tests were used to compare categorical variables. The number of treatments to remission/response was calculated.

Sixty-three adults with TRD, middle-aged (47.0 ± 12.1 years), predominantly female (65%), of which 76% (n = 48) and 24% (n = 15) received IV ketamine and IN esketamine, respectively. Mean (SE) change in QIDS-SR 16 score was −8.7 ± 0.7 (P < .001), a significant reduction (improvement) from baseline (mean ± SD = 17.6 ± 3.7). Overall remission and response rates were 36.5% and 55.6%, respectively in the acute phase. Response (56.3% vs 53.3%) and remission rates (39.6% vs 26.7%) were similar among patients who received IV ketamine or IN esketamine, respectively (P > .05). The mean number of treatments received to achieve response (2.5 ± 1.6 vs 4.6 ± 2.1) and remission (2.4 ± 1.3 vs 6.3 ± 2.4) were significantly lower among patients who received IV ketamine compared to IN esketamine (P < .005). Most patients tolerated both treatments well.

Intravenous ketamine and intranasal esketamine showed similar response/remission in TRD patients but the number of treatments required to achieve response/remission was significantly lower with IV ketamine compared to IN esketamine. These findings need to be investigated in a randomized control trial comparing these two treatment interventions.

No funding

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

This study examined healthcare utilization in the past year by subjects who screened positive for bipolar versus unipolar depression.

A self-administered survey was completed in 2002 by a United States population-based sample. Respondents were categorized into one of three subgroups: bipolar depressed screen positive (BP DEP+, n=394); unipolar depressed screen positive (UP DEP+, n=794); and control subjects (n=1,612).

For depressive symptoms in the past year, BP DEP+ respondents were significantly more likely than UP DEP+ respondents to report a healthcare visit to a number of diverse care providers. In analyses controlled for demographics and depression severity, the differences in psychiatric hospitalization, psychologist/counselor outpatient visit, substance abuse/social services visit, and number of emergency room visits remained significant between BP DEP+ and UP DEP+ respondents.

Subjects with self-reported bipolar depression sought care more often from a number of diverse healthcare resources than subjects with self-reported unipolar depression. These findings underscore the morbidity associated with bipolar depression.

The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.

To describe the rationale and methods of the SFBN.

The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.

The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilisers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.

Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.