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SummaryBipolar depression remains a major challenge for psychiatric therapeutics. It is associated with disability and excess mortality, and accounts for three-quarters of the time spent in morbid states by treated patients with bipolar disorder. Major limitations of research on the treatment of depression in bipolar disorder include a paucity of short-term and lack of long-term trials, probably reflecting concern about inducing mania. In addition, polytherapy with multiple drugs appears to be widespread, but it is virtually untested for efficacy and safety. Here, we summarise the evidence concerning efficacy of treatment of bipolar depression with antidepressants, mood-stabilising anticonvulsants, lithium and second-generation antipsychotics.LEARNING OBJECTIVES•Gain critical appreciation of the paucity of research on the treatment of bipolar depression.•Rationally balance the benefits and risks of using antidepressants in patients with bipolar disorder.•Assess the evidence supporting a range of research-based treatment options for bipolar depression.

Background Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. Methods Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8–48 (mean 18) years and aged 20–89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea–nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. Results Overall, 29.5% of subjects experienced at least one low value of eGFR ( 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m2. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. Limitations Control data for age-matched subjects not exposed to lithium were lacking. Conclusions Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.

Objective Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. Method We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. Results In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. Conclusion SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

Objective To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-item, second revision (HCL-32-R2) for the detection of bipolarity in major depressive disorder (MDD) treatment-seeking outpatients. Methods A back-to-back Italian adaption of the “Bipolar Disorders: Improving Diagnosis, Guidance, and Education” English module of the HCL-32-R2 was administered between March 2013 and October 2014 across twelve collaborating sites in Italy. Diagnostic and Statistical Manual Fourth edition (DSM-IV) diagnoses were made adopting the mini-international neuropsychiatric interview, using bipolar disorder (BD) patients as controls. Results In our sample ( n =441, of whom, BD-I=68; BD-II=117; MDD=256), using a cut-off of 14 allowed the HCL-32-R2 to discriminate DSM-IV-defined MDD patients between “true unipolar” (HCL-32-R2 − ) and “sub-threshold bipolar depression” (HCL-32-R2 + ) with sensitivity=89% and specificity=79%. Area under the curve was .888; positive and negative predictive values were 75.34% and 90.99% respectively. Owing to clinical interpretability considerations and consistency with previous adaptations of the HCL-32, a two-factor solution (F1=“ hyperactive / elated ” vs. F2=“ irritable / distractible / impulsive ”) was preferred using exploratory and confirmatory factor analyses, whereas items n.33 (“ I gamble more ”) and n.34 (“ I eat more ”) introduced in the R2 version of the scale slightly loaded onto F2 and F1 respectively. Cronbach׳s α=.88 for F1 and .71 for F2. Limitations No cross-validation with any additional validated screening tool; treatment-seeking outpatient sample; recall bias; no systematic evaluation of eventual medical/psychiatric comorbidities, current/lifetime pharmacological history, neither record of severity of current MDE. Conclusions Our results seem to indicate fair accuracy of HCL-32 as a screening instrument for BD, though replication studies are warranted.

The relationship between subclinical hypothyroidism and depression is still controversial. Our objective was to compare the prevalence of depressive symptoms and major depressive disorder in a population of patients affected by subclinical hypothyroidism and a control group without thyroid disease. The authors enrolled 123 consecutive outpatients affected by subclinical hypothyroidism undergoing follow-up at the endocrinology department of San Paolo Hospital in Milan and 123 controls without thyroid disease under the charge of general physicians.All patients and controls underwent an evaluation by means of a psychiatric interview; Hamilton Rating Scale for Depression (HAM-D); Montgomery-Asberg Depression Rating Scale (MADRS); and serum thyroid stimulating hormone, free T4, and free T3 levels. Patients were also screened for thyroid peroxidase antibodies and thyroglobulin antibodies. Patients affected by subclinical hypothyroidism had a prevalence of depressive symptoms of 63.4% at HAM-D and 64.2% at MADRS; 22 patients (17.9%) had a diagnosis of depressive episode (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria). The control group had a prevalence of depressive symptoms of 27.6% at HAM-D and 29.3% at MADRS, and only seven controls had a diagnosis of depressive episode. The prevalence of depressive symptoms between these two groups was statistically different. This study underlines a strong association between subclinical hypothyroidism and depressive symptoms, which could have some important diagnostic and therapeutic implications in the clinical practice.