Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial.

Objective: Therapeutic options are limited for treatment-resistant bipolar depression (TRBD). Insulin resistance (IR) confers increased risk for TRBD. We investigated metformin, an insulin sensitizer, to reverse IR and improve clinical outcomes in TRBD.Methods: Using a random-assignment (1:1), intent-to-treat, 2-site, quadruple-masked, parallel-group (metformin to 2,000 mg/d or placebo) clinical trial design, patients with DSM-5 bipolar disorder (BD) type I or II and IR received study medication for 26 weeks (February 2016 to October 2019). The primary outcome was the change in depression rating scores (Montgomery-Asberg Depression Rating Scale [MADRS]) at 14 weeks between those who no longer met IR criteria (converters) and those who still did (non-converters). Additional outcomes included scores on the Global Assessment of Functioning (GAF); the Clinical Global Impressions Scale, Bipolar Disorders version (CGI-BP); and the Hamilton Anxiety Rating Scale (HAM-A) and maintenance of improved outcomes up to 26 weeks.Results: Forty-five BD patients were randomized to metformin (n = 20) or placebo (n = 25), and at 14 weeks or later, 11 subjects no longer met IR criteria (n = 10 with metformin, n = 1 with placebo; P = .0009). These converters experienced significant improvements in MADRS (P values ranged from .031 to .008) and GAF (P values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A (P = .022 at week 14 and .019 at week 26) and CGI-BP change scores (P = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen d > 1 at 14 and 26 weeks) and large for the HAM-A and CGI-BP at 26 weeks. Transient gastrointestinal side effects occurred under both treatment conditions.Conclusions: Pending replication, this early study suggests that reversal of IR by metformin offers a path out of TRBD. Further characterization of metformin converters with TRBD will prove informative.Trial Registration: ClinicalTrials.gov identifier: NCT02519543.

Course of bipolar illness worsens after onset of insulin resistance.

Cross-sectional studies indicate that comorbid insulin resistance (IR) and type 2 diabetes are associated with a more severe course of bipolar disorder (BD); however, this relationship has not previously been assessed longitudinally. To address this, we reviewed health records of a case series of six patients with BD and comorbid IR. Severity and length of affective episodes (both mania and depression) over the lifetime were recorded using the Affective Morbidity Index; these data were obtained from ongoing prospective follow-up and from detailed retrospective chart reviews. All six patients with a previously episodic, relapsing-remitting course of illness experienced a worsening of morbidity after the onset of laboratory-demonstrated IR. These results suggest that IR may be a potential testable, modifiable factor in the progression of BD from a treatment responsive (episodic) to a non-responsive (chronic) course of illness.

Early-onset and very-early-onset bipolar disorder: distinct or similar clinical conditions?

OBJECTIVE: This study aimed to examine differences in the clinical presentation of very-early-onset (VEO) and early-onset (EO) bipolar disorder (BD) not fully explored previously. METHODS: We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode (VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 ± 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. RESULTS: In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. CONCLUSIONS: Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum.

Insulin resistance and outcome in bipolar disorder.

BACKGROUND: Little is known about the impact of insulin resistance on bipolar disorder. AIMS: To examine the relationships between insulin resistance, type 2 diabetes and clinical course and treatment outcomes in bipolar disorder. METHOD: 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. RESULTS: 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 sensitivity analyses. CONCLUSIONS: Comorbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder.

Genetic risk of suicidal behavior in bipolar spectrum disorder: analysis of 737 pedigrees.

OBJECTIVES: Suicide is a significant cause of mortality in patients with major affective disorders (MAD), and suicidal behavior and MAD co-aggregate in families. However, the transmission of suicidal behavior is partially independent from that of MAD. We analyzed the lifetime prevalence of completed and attempted suicides in a large sample of families with bipolar disorder (BD), its relation to family history of MAD and BD, and the contribution of clinical and treatment factors to the risk of suicidal behavior. METHODS: We studied 737 families of probands with MAD with 4919 first-degree relatives (818 affected, 3948 unaffected, and 153 subjects with no information available). Lifetime psychiatric diagnoses and suicidal behavior in first-degree relatives were assessed using semi-structured interviews, family history methods, and reviews of clinical records. Cox proportional hazard and logistic regression models were used to investigate the role of clinical covariates in the risk of suicidal behavior, and in the prevalence of MAD and BD. RESULTS: The estimated lifetime prevalence of suicidal behavior (attempted and completed suicides) in 737 probands was 38.4 ± 3.0%. Lithium treatment decreased suicide risk in probands (p = 0.007). In first-degree relatives, a family history of suicidal behavior contributed significantly to the joint risk of MAD and suicidal behavior (p = 0.0006). CONCLUSIONS: The liability to suicidal behavior is influenced by genetic factors (particularly family history of suicidal behavior and MAD). Even in the presence of high genetic risk for suicidal behavior, lithium treatment decreases suicide rates significantly.

An admixture analysis of the age at index episodes in bipolar disorder.

The interaction between polarity at onset (PAO) and age at onset (AAO) appears to be important for interpreting results of previous analyses of AAO in bipolar disorder (BD). Using an admixture analysis, we examined independently the distributions of age at first depressive and hypomanic/manic episodes in 379 BD I and II patients. Subsequently, we examined the association of PAO and AAO with specific clinical variables, using parametric and nonparametric analyses. Both depressive and manic onsets showed bimodal distributions. For depressive episodes, the means were: 18.5±4.1 (early onset) and 33.6±10.4 (late onset) years; and for manic episodes 18.9±3.3 (early onset) and 34.8±10.9 (late onset) years. For the overall AAO the best fit was for a mixture of three lognormal distributions (mean±S.D.): 15.5±2.0, 22.8±4.6, and 36.1±10.1years. Overall, an early onset was significantly associated with a chronic course of the disorder, a stronger family history of affective disorder, higher rates of rapid cycling, suicidal behavior, psychotic symptoms, and co-morbid anxiety disorders. Early onset depressive episodes were associated with higher rates of suicidal behavior and anxiety disorders, whereas early onset manic episodes were associated with psychotic symptoms and rapid cycling. Our results suggest the presence of a bimodal distribution of age at onset in BD according to the polarity of the index episode, and denote that an early onset BD, irrespective of polarity, may be a more serious subtype of the disorder.

Can body mass index help predict outcome in patients with bipolar disorder?

OBJECTIVE: Several studies have reported higher prevalence of obesity in patients suffering from bipolar disorder (BD). To study the relation of elevated body mass index (BMI) in patients with BD more closely, we investigated differences in sociodemographic, clinical, and medical characteristics with respect to BMI, with the hypothesis that BMI is related to prognosis and outcome. METHODS: We measured the BMI of 276 subjects of a tertiary care sample from the Maritime Bipolar Registry. Subjects were 16 to 83 years old, with psychiatric diagnoses of bipolar I disorder (n = 186), bipolar II disorder (n = 85), and BD not otherwise specified (n = 5). The registry included basic demographic data and details of the clinical presentation. We first examined the variables showing a significant association with BMI; subsequently, we modeled the relationship between BMI and psychiatric outcome using structural equation analysis. RESULTS: The prevalence of obesity in our sample was 39.1%. We found higher BMI in subjects with a chronic course (p < 0.001) and longer duration of illness (p = 0.02), lower scores on the Global Assessment of Functioning Scale (p = 0.02), and on disability (p = 0.002). Overweight patients had more frequent comorbid subthreshold social (p = 0.02) and generalized anxiety disorders (p = 0.05), diabetes mellitus type II (p < 0.001), and hypertension (p = 0.001). Subjects who achieved complete remission of symptoms on lithium showed significantly lower BMI (p = 0.01). CONCLUSIONS: Our findings suggest that BMI is associated with the prognosis and outcome of BD. Whether this association is causal remains to be determined.

Rapid cycling bipolar disorders in primary and tertiary care treated patients.

OBJECTIVE: Rapid cycling (RC) affects 13-30% of bipolar patients. Most of the data regarding RC have been obtained in tertiary care research centers. Generalizability of these findings to primary care populations is thus questionable. We examined clinical and demographic factors associated with RC in both primary and tertiary care treated populations. METHOD: Clinical data were obtained by interview from 240 bipolar I disorder (BDI) or bipolar II disorder (BDII) community-treated patients and by chart reviews from 119 bipolar patients treated at an outpatient clinic of a teaching hospital. RESULTS: Lifetime history of rapid cycling was present in 33.3% and 26.9% of patients from the primary and tertiary care samples, respectively. Among community-treated patients, lifetime history of RC was significantly associated with history of suicidal behavior and higher body mass index. There was a trend for association between RC and BDII, psychiatric comorbidity, diabetes mellitus, as well as lower age of onset of mania/hypomania. In the tertiary care treated sample there was a trend for association between lifetime history of RC and suicidal behavior. Tertiary versus primary care treated subjects with lifetime history of RC demonstrated markedly lower response to mood stabilizers. CONCLUSIONS: Lifetime history of RC is highly prevalent in both primary and tertiary settings. Even primary care treated subjects with lifetime history of RC seem to suffer from a more complicated and less treatment-responsive variant of bipolar disorder. Our findings further suggest relatively good generalizability of data from tertiary to primary care settings.

Clinical correlates of current level of functioning in primary care-treated bipolar patients.

OBJECTIVES: In this study we examined general assessment of functioning (GAF), and its relation to clinical and demographic factors in bipolar patients. A number of studies, mostly from specialized programs, show that bipolar disorder often leads to occupational and social impairment. Here we report data from patients in a primary care setting. METHODS: A total of 252 patients from the Maritime Bipolar Registry with DSM-IV diagnoses of bipolar I or bipolar II disorder participated in the study. GAF ratings during maintenance treatment were compared across clinical and demographic variables. RESULTS: The mean GAF score in this sample was 67 +/- 17 (range 10-100). The GAF scores followed bimodal distribution with mean values of 50.5 +/- 10.3 and 79.0 +/- 10.3. Decreased functioning was found in patients with chronic illness course, history of rapid cycling, suicidal behaviour, psychiatric comorbidity, hypothyroidism, and diabetes mellitus, regardless of treatment of these conditions. There were no differences in the level of functioning between men and women, bipolar I and II patients, those with and without psychotic episodes, hypertension, treatment with antidepressants or antipsychotics. CONCLUSIONS: Functioning in primary care-treated bipolar patients in maintenance phase of treatment is decreased not only due to specific disorder-related variables, but also due to frequent comorbidity with other psychiatric and medical conditions.

Pharmacogenetics and mood stabilization in bipolar disorder.

Bipolar disorder is a severe psychiatric disease characterized by varying treatment response among individual patients. Effects of certain treatments, for instance, lithium, can be predicted from clinical characteristics of patients and their family histories. This led to a suggestion that a treatment response could identify subtypes of bipolar disorder particularly suited for gene-mapping studies. In this paper we review family and molecular studies of bipolar disorder responsive to lithium, as well as studies aiming to identify polymorphisms associated with the treatment response itself. While molecular genetic research and gene expression studies promise to bring new insights into the pathophysiology of the illness and the nature of treatment response, and thus provide new information for better treatment of bipolar disorder in the future, results from family studies and studies of clinical correlates of treatment response may already be utilized in the management of bipolar disorder.

Clinical features of bipolar disorder with and without comorbid diabetes mellitus.

OBJECTIVE: Several papers have reported higher prevalence of diabetes mellitus (DM) type 2 in patients suffering from bipolar disorder (BD). The possible links between these 2 disorders include treatment, lifestyle, alterations in signal transduction, and possibly, a genetic link. To study this relation more closely, we investigated whether there are any differences in the clinical characteristics of BD patients with and without DM. METHOD: We compared the clinical data of 26 diabetic and 196 nondiabetic subjects from The Maritime Bipolar Registry. Subjects were aged 15 to 82 years, with psychiatric diagnoses of BD I (n = 151), BD II (n = 65), and BD not otherwise specified (n = 6). The registry included basic demographic data and details on the clinical course of bipolar illness, its treatment, and physical comorbidity. In a subsequent analysis using logistic regression, we examined the variables showing differences between groups, with diabetes as an outcome variable. RESULTS: The prevalence of DM in our sample was 11.7% (n = 26). Diabetic patients were significantly older than nondiabetic patients (P < 0.001), had higher rates of rapid cycling (P = 0.02) and chronic course of BD (P = 0.006), scored lower on the Global Assessment of Functioning Scale (P = 0.01), were more often on disability for BD (P < 0.001), and had higher body mass index (P < 0.001) and increased frequency of hypertension (P = 0.003). Lifetime history of treatment with antipsychotics was not significantly associated with an elevated risk of diabetes (P = 0.16); however, the data showed a trend toward more frequent use of antipsychotic medication among diabetic subjects. CONCLUSIONS: Our findings suggest that the diagnosis of DM in BD patients is relevant for their prognosis and outcome.