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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.
Decreased hippocampal volume reported in neuropsychiatric and endocrine disorders is considered a result of putative neuronal damage mediated by corticosteroids. This is the first prospective study of hippocampal volume and function in patients treated with corticosteroids.
14 subjects treated systemically with prednisone or betamethasone for dermatological or rheumatic disorders underwent prospective neurocognitive testing (Auditory Verbal Learning Test—AVLT, Trail Making Test—TMT, Digit Span—DS) and nine of them also repeated magnetic resonance volumetry.
The mean duration of treatment between the first and the second assessment was 73 ± 38 days with mean daily dose of 37 ± 17 mg prednisone and 193 ± 29 days, with mean daily dose of 24 ± 15 mg prednisone between the first and the third assessment. There was a trend towards decreases in total AVLT scores and an improvement in the TMT and DS, but no significant changes in the volumes of the right or the left hippocampi between the assessments. Prednisone dose did not correlate with the hippocampal volume change.
We observed a trend for decline in verbal memory despite improvement in psychomotor speed, attention/working memory and no macroscopic hippocampal volume changes during 36–238 days of treatment with therapeutic doses of corticosteroids.
Basic symptoms, defined as subjectively perceived disturbances in thought, perception and other essential mental processes, have been established as a predictor of psychotic disorders. However, the relationship between basic symptoms and family history of a transdiagnostic range of severe mental illness, including major depressive disorder, bipolar disorder and schizophrenia, has not been examined.
We sought to test whether non-severe mood disorders and severe mood and psychotic disorders in parents is associated with increased basic symptoms in their biological offspring.
We measured basic symptoms using the Schizophrenia Proneness Instrument – Child and Youth Version in 332 youth aged 8–26 years, including 93 offspring of control parents, 92 offspring of a parent with non-severe mood disorders, and 147 offspring of a parent with severe mood and psychotic disorders. We tested the relationships between parent mental illness and offspring basic symptoms in mixed-effects linear regression models.
Offspring of a parent with severe mood and psychotic disorders (B = 0.69, 95% CI 0.22–1.16, P = 0.004) or illness with psychotic features (B = 0.68, 95% CI 0.09–1.27, P = 0.023) had significantly higher basic symptom scores than control offspring. Offspring of a parent with non-severe mood disorders reported intermediate levels of basic symptoms, that did not significantly differ from control offspring.
Basic symptoms during childhood are a marker of familial risk of psychopathology that is related to severity and is not specific to psychotic illness.
It has been suggested that offspring of parents with bipolar disorder are at increased risk for disruptive mood dysregulation disorder (DMDD), but the specificity of this association has not been established.
We examined the specificity of DMDD to family history by comparing offspring of parents with (a) bipolar disorder, (b) major depressive disorder and (c) a control group with no mood disorders.
We established lifetime diagnosis of DMDD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children for DSM-5 in 180 youth aged 6–18 years, including 58 offspring of parents with bipolar disorder, 82 offspring of parents with major depressive disorder and 40 control offspring.
Diagnostic criteria for DMDD were met in none of the offspring of parents with bipolar disorder, 6 of the offspring of parents with major depressive disorder and none of the control offspring. DMDD diagnosis was significantly associated with family history of major depressive disorder.
Our results suggest that DMDD is not specifically associated with a family history of bipolar disorder and may be associated with parental depression.
Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.
We conducted a double-blind crossover study of a low dose (15 mg, ‘placebo’) and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.
Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.
The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery–Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.
Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.
Little is known about the impact of insulin resistance on bipolar
To examine the relationships between insulin resistance, type 2 diabetes
and clinical course and treatment outcomes in bipolar disorder.
We measured fasting glucose and insulin in 121 adults with bipolar
disorder. We diagnosed type 2 diabetes and determined insulin resistance.
The National Institute of Mental Health Life Chart was used to record the
course of bipolar disorder and the Alda scale to establish response to
prophylactic lithium treatment.
Patients with bipolar disorder and type 2 diabetes or insulin resistance
had three times higher odds of a chronic course of bipolar disorder
compared with euglycaemic patients (50% and 48.7% respectively
v. 27.3%, odds ratio (OR) = 3.07, P
= 0.007), three times higher odds of rapid cycling (38.5% and 39.5%
respectively v. 18.2%, OR = 3.13, P =
0.012) and were more likely to be refractory to lithium treatment (36.8%
and 36.7% respectively v. 3.2%, OR = 8.40,
P<0.0001). All associations remained significant
after controlling for antipsychotic exposure and body mass index in
Comorbid insulin resistance may be an important factor in resistance to
treatment in bipolar disorder.
We studied the course of major mood disorders in the offspring of parents with well-characterised bipolar disorder prospectively for up to 15 years. All consenting offspring were assessed annually or anytime symptomatic. The participants began to develop major mood episodes in adolescence and not before. The index major mood episode was almost always depressive, as were the first few recurrences. Onsets and recurrences continued throughout the observation period into adulthood. We did not find evidence of pre-pubertal mania. In summary, adolescence marks the beginning of the high-risk period for major mood episodes related to bipolar disorder.
La disminución del volumen del hipocampo comunicada en trastornos neuropsiquiátricos y endocrinos se considera resultado de un daño neuronal putativo mediado por corticoesteroides. Éste es el primer estudio prospectivo del volumen y la función del hipocampo en pacientes tratados con corticoesteroides.
Se sometió a 14 sujetos tratados sistémicamente con prednisona o betametasona por trastornos dermatológicos o reumáticos a pruebas neurocognitivas prospectivas (Prueba de Aprendizaje Verbal Auditivo [AVLT], Prueba del Trazo [TMT], Amplitud de dígitos [AD]) y nueve de ellos repitieron también una volumetría de resonancia magnética.
La duración media del tratamiento entre la primera evaluación y la segunda fue 73 ± 38 días con dosis diaria media de 37 ± 17 mg de prednisona y 193 ± 29 días, con dosis diaria media de 24 ± 15 mg de prednisona, entre la primera evaluación y la tercera. Hubo una tendencia a disminuciones en las puntuaciones totales de la AVLT y una mejoría en la TMT y la AD, pero ausencia de cambios significativos en el volumen de los hipocampos derecho o izquierdo entre las evaluaciones. La dosis de prednisona no correlacionaba con el cambio de volumen del hipocampo.
Observamos una tendencia a la disminución en la memoria verbal a pesar de la mejora en la velocidad psicomotriz, la atención/memoria operativa y una ausencia de cambios del volumen macroscópico del hipocampo durante los 36-238 días de tratamiento con dosis terapéuticas de corticoesteroides.
Response to long-term lithium treatment in bipolar disorder appears to be related to the family history of a patient. Conversely, some studies have indicated that treatment response could identify a subtype of bipolar disorder characterized by a stronger role of genetic factors and possibly by major-gene effects. Several groups have now conducted molecular genetic studies in order to identify genes contributing to the etiology of bipolar disorder as well as genes that may influence long-term treatment response. There is limited evidence that the response to mood stabilizers could be individually specific. This chapter focuses on individual treatments, in particular on lithium for which the most data are available. Subsequently, several other studies found an association between prophylactic lithium response and a family history of bipolar disorder. The chapter presents a study of patients with bipolar disorder responsive to lithium in collaboration with the International Group for Study of Lithium (IGSLI).
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