Microcytic Anaemia as Susceptibility Factors in Bipolar Spectrum Disorders: Review of the Literature, Replication Survey, and Co-Segregation within Families.

BACKGROUND: Potential interactions between mood disorders and microcytic anaemias have been suggested by case reports, surveys of haematological parameters in psychiatric populations, and surveys of psychiatric morbidity in thalassaemic carriers. OBJECTIVES: a) To review published studies.b) To study the prevalence of microcytic anaemia in a sample of Sardinian outpatients with recurrent mood disorders.c) To check whether mood disorders and microcytic anaemia co-segregate within families. METHODS: We extracted data on blood count and serum iron concentrations from the records of patients admitted between January 1st, 2001 and December 31st, 2016, to our clinic for mood disorders. Moreover, we studied siblings of subjects with both major mood disorders (according to Research Diagnostic Criteria) and heterozygous thalassaemia (according to Mean Corpuscular Volume, serum iron, and haemoglobin A2 concentrations). Siblings affected with a major mood disorder were examined for haematological concordance with the proband (reduced MCV and/or increased HbA2 in case of heterozygous ß-thalassaemia, or presence of gene deletions in case of α-thalassaemia). RESULTS: Microcytic anaemia was highly prevalent (81/337 = 24.0%) among outpatients with mood disorders. Starting from 30 probands with heterozygous ß-thalassaemia, concordance for reduced MCV and/or increased HbA2 was found in 78% (35/45) of affected siblings. Starting from 3 probands with heterozygous α-thalassaemia, only one of the 5 affected siblings carried four α-globin functional genes. CONCLUSION: Based on the review of the literature, the high prevalence of microcytic anaemia in outpatients, and the concordance between affected siblings, we can conclude that a role of heterozygous thalassaemias is highly probable. Future studies are required to establish the relevance of heterozygous thalassaemias and evaluate the magnitude of the effect, possibly using a molecular diagnosis also in the case of heterozygous ß-thalassaemia.

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder.

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications.

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F6, 137 = 20.128, p = 8.73 × 10-17, effect of diagnosis, F3 = 31.870; p = 1.08 × 10-15). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

A multidisciplinary approach to mental illness: do inflammation, telomere length and microbiota form a loop? A protocol for a cross-sectional study on the complex relationship between inflammation, telomere length, gut microbiota and psychiatric disorders.

INTRODUCTION: Severe psychiatric disorders are typically associated with a significant reduction in life expectancy compared with the general population. Among the different hypotheses formulated to explain this observation, accelerated ageing has been increasingly recognised as the main culprit. At the same time, telomere shortening is becoming widely accepted as a proxy molecular marker of ageing. The present study aims to fill a gap in the literature by better defining the complex interaction/s between inflammation, age-related comorbidities, telomere shortening and gut microbiota in psychiatric disorders. METHODS AND ANALYSIS: A cross-sectional study is proposed, recruiting 40 patients for each of three different diagnostic categories (bipolar disorder, schizophrenia and major depressive disorder) treated at the Section of Psychiatry and at the Unit of Clinical Pharmacology of the University Hospital Agency of Cagliari (Italy), compared with 40 age-matched and sex-matched non-psychiatric controls. Each group includes individuals suffering, or not, from age-related comorbidities, to account for the impact of these medical conditions on the biological make-up of recruited patients. The inflammatory state, microbiota composition and telomere length (TL) are assessed. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2018/11693, 5 September 2018). The study is conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki, and in compliance with the relevant Italian national legislation. Written, informed consent is obtained from all participants. Participation in the study is on a voluntary basis only. Patients will be part of the dissemination phase of the study results, during which a local conference will be organised and families of patients will also be involved. Moreover, findings will be published in one or more research papers and presented at national and international conferences, in posters or oral communications.

Internet use by older adults with bipolar disorder: international survey results.

BACKGROUND: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. METHODS: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. RESULTS: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. CONCLUSIONS: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Thyroid and renal tumors in patients treated with long-term lithium: case series from a lithium clinic, review of the literature and international pharmacovigilance reports.

BACKGROUND: Cancer had never been considered as a relevant problem in patients treated with lithium until 2015, when a document published by the European Medicine Agency concluded that long-term use of lithium might induce renal tumors. A few months later, we observed the case of a woman treated with lithium for 18 years who was diagnosed with both thyroid and renal tumors. METHODS: This study aimed to investigate the correlation between lithium treatment and thyroid or renal tumors. We analyzed clinical records in our lithium clinic database, causes of death of patients who had been visited at least once at the lithium clinic, reports of lithium adverse reactions in the European and WHO pharmacovigilance databases, and published cases of thyroid and renal tumors in long-term lithium-treated patients. RESULTS: Of the 1871 lithium patients who had been visited at least once between 1980 and 2013, eight had been diagnosed with thyroid papillary carcinoma and two with clear-cell renal-cell carcinoma. No cases of thyroid cancer and only one case of renal tumor were the cause of death according to the 375 available death certificates. VigiAccess database contained a total of 29 and 14 cases of renal and thyroid tumors, respectively. EudraVigilance database contained 21 cases of renal and 8 of thyroid neoplasms. Literature search yielded 6 published cases of thyroid papillary carcinoma and 25 cases of various renal tumors. However, two population-based studies did not find any increased risks of cancer in patients exposed to lithium, whereas two nationwide studies did not find any excess of renal tumors. CONCLUSION: So far it has not been possible epidemiologically to confirm an increased risk of thyroid or renal cancers associated with lithium. Such a conclusion is supported by the findings of low rates and mortalities of thyroid or renal cancers from the present lithium clinic data.

Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study.

BACKGROUND: Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. METHODS: We studied 394 patients who were treated with lithium for ≥ 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with L-thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan-Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. RESULTS: Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. CONCLUSIONS: The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients.

Psychotropic Medication of Acute Episodes of Mood Disorders: Current Prescription Attitude in Two Psychiatric Wards in Cagliari, Italy.

BACKGROUND: Medication of acute episodes of mood disorders has changed over the last decades following the results of randomized clinical trials. OBJECTIVE: The aim of this study was to analyze medication prescribed at discharge from two psychiatric wards. We focused on hospitalization as one of the best opportunities to start prophylaxis. METHODS: We examined retrospectively the clinical records of 357 patients hospitalized for mood episodes in two psychiatric wards in the Cagliari area (SPDC-1 and SPDC-2) between 1 January and 31 December 2016. We focused on the psychotropic medication prescribed at discharge from the hospital. RESULTS: Most patients were discharged with antipsychotics (86%) and/or benzodiazepines (89%). Combined medication was frequent, including various co-administration of first-generation and/or second-generation antipsychotics (26% of patients), or antipsychotics combined with mood-stabilizers (51% of patients). There was a preferential prescription of first-generation antipsychotics in SPDC-1, and of second-generation antipsychotics in SPDC-2. Prescription of lithium was significantly more frequent in SPDC-1. CONCLUSION: Although the treatment was in line with randomized clinical trials, the choice of individual psychotropic agents differed significantly between the two wards. Different prescription attitudes can have consequences on the long-term outcome of patients discharged from the hospital after an acute mood episode.

International multi-site survey on the use of online support groups in bipolar disorder.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters.

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 (<60 mL/min/1.73 m2), most after ≥15 years of treatment and age > 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.

An observational study of 110 elderly lithium-treated patients followed up for 6 years with particular reference to renal function.

BACKGROUND: Recent observational studies have focused on lithium treatment in the elderly, with particular reference to safety in terms of thyroid and renal functions. The purpose of this study was to compare the clinical characteristics of patients starting lithium treatment before (N = 79) or after (N = 31) the age of 65 years. Patients were followed up for 6 years with focus on renal function and prescription of levothyroxine and methimazole. RESULTS: At baseline, median lithium serum concentration was 0.55 mmol/l. The estimated glomerular filtration rate was lower than 60 ml/min/1.73 m2 in 43 (39%) patients. In a multiple regression analysis controlling for age and gender, we found a significant effect of duration of lithium treatment on estimated glomerular filtration rate (-0.85 ml/min/1.73 m2 per year of prior exposure). The annual decline during follow-up was 2.3 ml/min/1.73 m2. Two patients were prescribed levothyroxine, and two were prescribed methimazole for the first time during follow-up. CONCLUSIONS: Median lithium serum concentration in this cohort of elderly patients with mainly bipolar disorders was lower than the therapeutic range indicated for younger adults. The decline in glomerular filtration rate may be accelerated by long-term lithium use. Thyroid and renal functions continue to require close monitoring throughout the course of lithium treatment. Trial registration NP/2013/3836. Registered 24 June 2013.

Interstitial lung disease induced by fluoxetine: Systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database.

We investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as "pulmonary disease". Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs.

The Sardinian Puzzle: Concentration of Major Psychoses and Suicide in the Same Sub-Regions Across One Century.

BACKGROUND: Sardinia, the second largest Mediterranean island has long been considered a privileged observatory for the study of several medical conditions. The peculiar epidemiology of mood disorders and suicide across Sardinian sub-regions has long intrigued clinicians and researchers. OBJECTIVE: The principal aim of the present study was to test whether the geographical distribution of suicides committed in Sardinian over the last three decades are comparable with the geographical origin of patients hospitalized up to half a century ago. METHOD: The distribution of the municipalities of origin of the patients hospitalized in Sardinia between 1901 and 1964 for schizophrenia, bipolar disorder, and depression was reanalyzed and compared with the distribution of municipalities where suicides were committed between 1980 and 2013. Data were also analyzed by the altitude above the sea level and by the population size of the municipalities. RESULTS: There was a significant variation of hospitalization and suicide rates across Sardinian sub-regions. The sub-regions of origin of the patients hospitalized for schizophrenia and bipolar disorder correlated with each other (P = 0.047). Both hospitalizations and suicides were more incident in municipalities with a higher altitude and a smaller population size. The incidence of hospitalizations and suicides correlated significantly with each other both at the municipality (P = 1.86 x 10-7) and at the sub-region level (P = 1.71 x 10-7). CONCLUSION: The present study confirms the peculiar geographical distribution of major psychoses and suicide in Sardinia. The two phenomena appear to have been correlated for as long as one century.

Pharmacogenetics of lithium effects on glomerular function in bipolar disorder patients under chronic lithium treatment: a pilot study.

Bipolar disorder (BD) is a psychiatric disease characterized by alternating episodes of mania and depression. Lithium (Li) represents the mainstay treatment for BD, although a significant proportion of patients shows insufficient or no response. Li is also associated with potentially severe side effects, including renal effects. Several studies reported that Li may induce reduction of glomerular filtration rate (GFR) in patients under long-term treatment. The biological systems and the genetic factors involved in susceptibility to Li-induced renal-side effects have been scarcely explored. The aim of our study was to test the contribution of putatively risk genetic variants in Li-induced reduction in estimated GFR (eGFR) in BD patients under long-term Li treatment. Tag SNPs, located in genes previously shown to be associated with kidney dysfunction or Li mechanism of action, were selected and genotyped in a sample of 70 BD patients of Sardinian origin. SNP rs378448, located in Acid Sensing Ion Channel Neurona-1 (ACCN1) gene, showed a significant interaction with duration of Li treatment on eGFR (F2=3.623, p=0.033). Our preliminary findings suggest that rs378448 could predispose BD subjects to a detrimental effect of chronic Li treatment on kidney functioning.

Online information seeking by patients with bipolar disorder: results from an international multisite survey.

BACKGROUND: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. METHODS: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. RESULTS: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. CONCLUSION: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Internet use by patients with bipolar disorder: Results from an international multisite survey.

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.