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Background: Few studies have reported real-life data on socio-economic functioning in patients with bipolar disorder and their unaffected first-degree relatives., Methods: We used Danish nation-wide population-based longitudinal register linkage to investigate socio-economic functioning in 19 955 patients with bipolar disorder, their 13 923 siblings and 20 sex, age and calendar-matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Patients with a diagnosis of bipolar disorder had lower odds of having achieved the highest educational level [OR 0.75 (95% confidence interval (CI) 0.73-0.77)], being employed [OR 0.16 (95% CI 0.159-0.168)], having achieved the 80% highest quartile of income [OR 0.33 (95% CI 0.32-0.35)], cohabitating [OR 0.44 (95% CI 0.43-0.46)] and being married [OR 0.54 (95% CI 0.52-0.55)] at first contact to hospital psychiatry as inpatient or outpatient compared with control individuals from the general population. Similarly, siblings to patients with bipolar disorder had a lower functioning within all five socio-economic areas than control individuals. Furthermore, patients and partly siblings showed substantially decreased ability to enhance their socio-economic functioning during the 23 years follow-up compared to controls., Conclusions: Socio-economic functioning is substantially decreased in patients with bipolar disorder and their siblings and does not improve during long-term follow-up after the initial hospital contact, highlighting a severe and overlooked treatment gap.

Objective: Mortality is increased in bipolar disorder due to both suicide and death by physical disorders, but it has never been investigated whether these mortalities translate into relatives to patients with bipolar disorder. The aim was to present the life expectancy and the overall mortality and mortality due to suicide and physical disorders among patients with bipolar disorder and their unaffected full siblings, respectively, compared with control individuals from the general population., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 19.955 patients with bipolar disorder, their 13.923 siblings and 20 sex, age and calendar matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Bipolar disorder was associated with a decreased life expectancy of 7.7 (95% CI: 7.4-8.1) years and increased mortality overall (hazard ratio (HR): 2.11 (95% CI: 2.04-2.18)) and due to suicide (HR: 18.23 (95% CI: 15.81-21.02) and physical disorders (HR: 2.01 (95% CI: 1.94-2.08). In contrast, siblings to patients with bipolar disorder who were unaffected by bipolar disorder did not have decreased life expectancy (0.45 (95% CI: -6.62-2.46)) or increased mortality overall (HR: 1.00 (95% CI: 0.88-1.14) or due to suicide (HR: 1.50 (95% CI: 0.95-2.36) or physical disorders (HR: 0.99 (95% CI: 0.87-1.34)., Conclusions: Increased mortality in bipolar disorder is mainly due to the impact of bipolar psychopathology and to a lesser degree to familial transmitted factors, highlighting the urgent need for preventive intervention studies in relation to suicide and physical disorders following onset of bipolar disorder., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The aim was to map rates and cumulative incidences of psychiatric disorders during lifetime for siblings to patients with a diagnosis of bipolar disorder compared with the general population., Methods: Danish nationwide population-based longitudinal register linkage study including 13,923 unaffected siblings to 19,955 patients with bipolar disorder and 278,460 unaffected control individuals from the general population matched according to year of birth and sex. Follow-up covered 22 years from 1995 to 2017., Results: Rates of 'any psychiatric disorder' among siblings compared with control individuals were constantly around twofold increased throughout lifespan whereas there was a bimodal age distribution of hazard ratios of bipolar disorder, unipolar disorder and use of alcohol or psychoactive drugs with the highest hazard ratios up to age 20 and above 60 years of age. Cumulative incidences from age 15 years of any psychiatric disorder were 44.2% at age 80 years for siblings versus 27.6% for control individuals and the corresponding numbers for bipolar disorder was 8.7% for siblings compared with 1.6% for control individuals., Conclusion: Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifetime, likely with differentiated age-specific strategies., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with bipolar disorder may have increased risk of physical diseases due to genetic and environmental factors, but no study has systematically mapped all physical comorbidities in such subjects. The aim was to map rates of all physical diseases among patients and siblings to patients with bipolar disorder., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 19.955 patients with bipolar disorder, their 13.923 siblings and 20 sex, age and calendar matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Bipolar disorder was associated with increased rates of all physical disease categories compared with rates for control individuals, except for cancer. Further, bipolar disorder was associated with increased rates of separate disorders including ischemic heart disease, diabetes, dementia, hypertension, hypercholesterolemia and hyperlipidemia, hypothyroidism and infections. In contrast, siblings to patients with bipolar disorder who were unaffected by bipolar disorder had increased rates of certain disorders, only, comprising infectious and parasitic diseases, and diseases of the nervous system, digestive system and genitourinary system., Limitations: Underdetection of physical disorders is likely because data are not available for persons who do not seek help for their disorders., Conclusions: Bipolar disorder was associated with increased rates of all physical diseases categories, except cancer, and with separate disorders, likely involving inflammatory components in the pathogenesis. In contrast, unaffected siblings to patients with bipolar disorder had increased rates of certain disorders, only., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation-wide population-based registers to investigate whether continued use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, high-dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder., Methods: A nation-wide population-based longitudinal study using Poisson regression analyses including all persons in Denmark who purchased the exposure medication of interest and a random sample of 30% of the Danish population. The follow-up period comprised a 10 years period from 2005 to 2015. Two different outcome measures were included, (1) a diagnosis of mania/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of a diagnosis of mania/bipolar disorder or initiation of lithium use., Results: A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015, median age 57 years [quartiles: 43;69], and female proportion of 53.1%. Continued use of low-dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder on both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident bipolar disorder. There were no statistically significant associations for allopurinol., Conclusions: The study supports the potential of agents acting on inflammation and the stress response system in bipolar disorder and illustrates that population-based registers can be used to systematically identify drugs with repurposing potentials., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: For the first time to estimate the risk of recurrence among patients with a single manic/mixed episode by systematically reviewing prior studies on cohorts of adults, and cohorts of children and adolescents, respectively., Methods: A systematic literature search up to August 2017 was carried out including studies in which < 25% of the participants were estimated to have had a mood episode that required pharmacological treatment prior to the index manic or mixed episode at inclusion., Results: Three studies including a total of 293 adult patients with a single manic or mixed episode and three studies of children and adolescents including 126 patients were identified. In the adult studies, 31%, 40% and 42% experienced recurrence after recovery within 1 year, 59% after 2 years, and 58% after 4 years, respectively. In the studies on children and adolescents, 40% and 52% experienced recurrence after recovery within 1 year, 30% and 60% after 2 years and 64% and 67% after 4 to 5 years, respectively. Results from meta-analyses showed a 1-year rate of recurrence of 35% (95% confidence interval [CI]: 30-41%) in adults, and in adolescents/children, a 1-year rate of recurrence of 48% (95% CI: 38-58%), a 2-year rate of 46% (95% CI: 33-60%) and a 4-5-year rate of recurrence of 65% (95% CI: 52-77%; as data from different studies were included at 1, 2 and 5 years, rates of recurrence did not increase steadily with time)., Conclusions: The rate of recurrence is high among adults as well as children and adolescents. It is important that clinicians and patients as well as relatives are well informed about these high risks when deciding to start maintenance treatment or not following onset of a single manic or mixed episode., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder., Methods: We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals., Results: The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 μg/L; interquartile range [IQR]: 7.9-15.5 μg/L) and controls (12.5 μg/L; IQR: 7.6-15.7 μg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age)., Conclusion: Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: For the first time to present a systematic review and meta-analysis of the conversion rate and predictors of conversion from unipolar disorder to bipolar disorder., Methods: A systematic literature search up to October 2016 was performed. For the meta-analysis, we only included studies that used survival analysis to estimate the conversion rate., Results: A total of 31 studies were identified, among which 11 used survival analyses, including two register-based studies. The yearly rate of conversion to bipolar disorder decreased with time from 3.9% in the first year after study entry with a diagnosis of unipolar disorder to 3.1% in years 1-2, 1.0% in years 2-5 and 0.8% in years 5-10. A total of eight risk factors were evaluated comprising gender, age at onset of unipolar disorder, number of depressive episodes, treatment resistance to antidepressants, family history of bipolar disorder, the prevalence of psychotic depression, the prevalence of chronic depression, and severity of depression. It was not possible to identify risk factors that were consistently or mainly confirmed to predict conversion across studies., Conclusions: The conversion rate from unipolar to bipolar disorder decreases with time. It was not possible to identify predictors of conversion that were consistently or mainly confirmed across studies, which may be due to variations in methodology across studies., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: It is a widely held belief that affective disorders are progressive of nature; however, some recent reviews have questioned this belief. The objective of the present systematic literature review was to present evidence for associations between number of affective episodes and (i) the risk of recurrence of episodes, (ii) probability of recovery from episodes, (iii) severity of episodes, (iv) the threshold for developing episodes, and (v) progression of cognitive deficits in unipolar and bipolar disorders., Method: A systematic review comprising an extensive literature search conducted in Medline, Embase, and PsychInfo up to September 2016 and including cross-references from identified papers and reviews., Results: Most of the five areas are superficially investigated and hampered by methodological challenges. Nevertheless, studies with the longest follow-up periods, using survival analysis methods, taking account of the individual heterogeneity all support a clinical progressive course of illness. Overall, increasing number of affective episodes seems to be associated with (i) increasing risk of recurrence, (ii) increasing duration of episodes, (iii) increasing symptomatic severity of episodes, (iv) decreasing threshold for developing episodes, and (v) increasing risk of developing dementia., Conclusion: Although the course of illness is heterogeneous, there is evidence for clinical progression of unipolar and bipolar disorders., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In depression, non-remission, recurrence of depressive episodes after remission and conversion to bipolar disorder are crucial determinants of poor outcome. The present study aimed to determine the cumulative incidences and clinical predictors of these long-term outcomes after the first lifetime episode of depression., Method: A total of 301 in- or out-patients aged 18-70 years with a validated diagnosis of a single depressive episode were assessed from 2005 to 2007. At 5 years of follow-up, 262 patients were reassessed by means of the life chart method and diagnostic interviews from 2011 to 2013. Cumulative incidences and the influence of clinical variables on the rates of remission, recurrence and conversion to bipolar disorder, respectively, were estimated by survival analysis techniques., Results: Within 5 years, 83.3% obtained remission, 31.5% experienced recurrence of depression and 8.6% converted to bipolar disorder (6.3% within the first 2 years). Non-remission increased with younger age, co-morbid anxiety and suicidal ideations. Recurrence increased with severity and treatment resistance of the first depression, and conversion to bipolar disorder with treatment resistance, a family history of affective disorder and co-morbid alcohol or drug abuse., Conclusions: The identified clinical characteristics of the first lifetime episode of depression should guide patients and clinicians for long-term individualized tailored treatment.

Objectives: The aim of the present study was to describe prescription patterns and changes in these patterns over the last decade for patients diagnosed with bipolar disorder in mental healthcare, using population-based and nationwide data, and to relate the findings to recommendations from international guidelines., Methods: A population-based, nationwide study was carried out. It included register-based longitudinal data on all patients with a first-ever contact with mental healthcare with a diagnosis of mania/bipolar disorder from the entire Danish population, and all prescription data for this population during the decade from 2000 to 2011, inclusive., Results: A total of 3,205 patients were included in the study. Lithium was prescribed less, and antiepileptic and atypical antipsychotic agents were prescribed substantially more during the study period. Lithium went from being the first drug prescribed to being the last, and was replaced by atypical antipsychotic agents. Antiepileptic agents went from being the fourth to the second drug class prescribed, and the prescription of antidepressants was virtually unchanged, at a high level, during the decade (one-year value 40-60%). The prescription of lamotrigine and quetiapine increased substantially. Combination therapy increased for all drug combinations, except for lithium combined with antidepressants., Conclusions: Major changes took place in drug prescriptions during the study period. The decrease in the use of lithium and the constant high use of antidepressants do not align with recommendations from international guidelines., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals., Methods: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder., Results: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder., Conclusions: Treatment with lithium is not associated with increased rates of RUT., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Life expectancy in patients with bipolar disorder has been reported to be decreased by 11 to 20 years. These calculations are based on data for individuals at the age of 15 years. However, this may be misleading for patients with bipolar disorder in general as most patients have a later onset of illness. The aim of the present study was to calculate the remaining life expectancy for patients of different ages with a diagnosis of bipolar disorder., Methods: Using nationwide registers of all inpatient and outpatient contacts to all psychiatric hospitals in Denmark from 1970 to 2012 we calculated remaining life expectancies for values of age 15, 25, 35 ⃛ 75 years among all individuals alive in year 2000., Results: For the typical male or female patient aged 25 to 45 years, the remaining life expectancy was decreased by 12.0-8.7 years and 10.6-8.3 years, respectively. The ratio between remaining life expectancy in bipolar disorder and that of the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood., Conclusions: Life expectancy in bipolar disorder is decreased substantially, but less so than previously reported. Patients start losing life-years during early and mid-adulthood., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Accelerated aging has been proposed as a mechanism explaining the increased prevalence of comorbid general medical illnesses in bipolar disorder., Aims: To test the hypothesis that lost life years due to natural causes starts in early and mid-adulthood, supporting the hypothesis of accelerated aging., Methods: Using individual data from nationwide registers of patient with a diagnosis of bipolar disorder we calculated remaining life expectancies before age 90 years for values of age 15, 25, 35…75 years among all individuals alive in year 2000. Further, we estimated the reduction in life expectancy due to natural causes (physical illnesses) and unnatural causes (suicide and accidents) in relation to age., Results: A total of 22,635 patients with bipolar disorder were included in the study in addition to data from the entire Danish general population of 5.4 million people. At age 15 years, remaining life expectancy before age 90 years was decreased 12.7 and 8.9 life years, respectively, for men and women with bipolar disorder. For 15-year old boys with bipolar disorder, natural causes accounted for 58% of all lost life years and for 15-year old girls, natural causes accounted for 67% increasing to 74% and 80% for 45-year old men and women, respectively., Limitations: Data concern patients who get contact to hospital psychiatry only., Conclusions: Natural causes of death is the most prevalent reason for lost life years already from adolescence and increases substantially during early and mid-adulthood, in this way supporting the hypothesis of accelerated aging. Early intervention in bipolar disorder should not only focus on improving outcome of the bipolar disorder but also on decreasing the risk of comorbid general medical illnesses., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: No study has investigated when preventive treatment with lithium should be initiated in bipolar disorder., Aims: To compare response rates among patients with bipolar disorder starting treatment with lithium early v. late., Method: Nationwide registers were used to identify all patients with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium during the period 1995-2012 in Denmark (n = 4714). Lithium responders were defined as patients who, following a stabilisation lithium start-up period of 6 months, continued lithium monotherapy without being admitted to hospital. Early v. late intervention was defined in two ways: (a) start of lithium following first contact; and (b) start of lithium following a diagnosis of a single manic/mixed episode., Results: Regardless of the definition used, patients who started lithium early had significantly decreased rates of non-response to lithium compared with the rate for patients starting lithium later (adjusted analyses: first v. later contact: P<0.0001; hazard ratio (HR) = 0.87, 95% CI 0.76-0.91; single manic/mixed episode v. bipolar disorder: P<0.0001; HR = 0.75, 95% CI 0.67-0.84)., Conclusions: Starting lithium treatment early following first psychiatric contact or a single manic/mixed episode is associated with increased probability of lithium response., (Royal College of Psychiatrists.)

It is not clear whether the effectiveness of lamotrigine versus lithium differs for patients with bipolar disorder treated in clinical practice. We compared rates of switch to, or add on of, another psychotropic, and rates of psychiatric hospitalization for patients treated with lamotrigine or lithium in clinical practice. Using linkage of nationwide Danish registers we identified 730 patients who received lamotrigine and 3518 patients received lithium subsequent to a diagnosis of bipolar disorder in psychiatric hospital settings during a period from 1995 to 2006. The overall rate of switch to or add on of another psychotropic (the opposite drug of interest (lithium or lamotrigine), antidepressants, antipsychotics or other anticonvulsants than lamotrigine) was increased for lamotrigine compared with lithium (HR = 2.60, 95% CI: 2.23-3.04), regardless of whether the index episode was depressive, manic, mixed or remission. In addition, the overall rate of psychiatric hospitalization was increased for lamotrigine compared with lithium (HR = 1.45, 95% CI: 1.28-1.65), as were the rates for patients with a depressive (HR = 1.31, 95% CI: 1.01-1.70) and patients with a manic (HR = 1.65, 95% CI: 1.31-2.09) index episode. Rates did not differ significantly between the drugs for patients with a mixed index episode and for patients in remission. It is concluded that in daily clinical practice, treatment with lithium is in general superior to treatment with lamotrigine.

The aim of this study was to identify sociodemographic and clinical predictors of excellent response, that is, 'cure' of future affective episodes, to lithium in monotherapy. We used nationwide registers to identify all patients with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium from 1995 to 2006 in Denmark (N=3762). Excellent lithium responders were defined as patients who after a stabilization lithium start-up period of 6 months, continued lithium in monotherapy without getting hospitalized. The rate of excellent response to lithium in monotherapy was 8.9% [95% confidence interval (CI): 7.9-9.9] at 5-year follow-up and 5.4% (95% CI: 4.4-6.3) at 10-year follow-up. The rate of nonresponse to lithium monotherapy was significantly increased for female patients [hazards ratio (HR)=1.12, 95% CI: 1.04-1.21) and for patients with a depressive index episode compared with patients in remission or with a diagnosis of other or unspecified bipolar disorder before first lithium purchase (HR=1.13, 95% CI: 1.03-1.25). The rate of nonresponse increased by 3% (95% CI: 2-5%) for every psychiatric hospitalization before first purchase of lithium. Patients with somatic comorbidity had increased rates of non-response to lithium compared with patients without somatic comorbidity (HR=1.23, 95% CI: 1.00-1.52).It is concluded that the prevalence of excellent response to lithium monotherapy is low and such patients are characterized by few earlier psychiatric hospitalizations, a manic index episode before lithium and reduced somatic comorbidity.

Background: Valproate is one of the most used mood stabilisers for bipolar disorder, although the evidence for the effectiveness of valproate is sparse., Aims: To compare the effect of valproate v. lithium for treatment of bipolar disorder in clinical practice., Method: An observational cohort study with linkage of nationwide registers of all people with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed valproate or lithium in Denmark during a period from 1995 to 2006., Results: A total of 4268 participants were included among whom 719 received valproate and 3549 received lithium subsequent to the diagnosis of bipolar disorder. The rate of switch/add on to the opposite drug (lithium or valproate), antidepressants, antipsychotics or anticonvulsants (other than valproate) was increased for valproate compared with lithium (hazard ratio (HR) = 1.86, 95% CI 1.59-2.16). The rate of psychiatric hospital admissions was increased for valproate v. lithium (HR = 1.33, 95% CI 1.18-1.48) and regardless of the type of episode leading to a hospital admission (depressive or manic/mixed). Similarly, for participants with a depressive index episode (HR = 1.87, 95% CI 1.40-2.48), a manic index episode (HR = 1.24, 95% CI 1.01-1.51) and a mixed index episode (HR = 1.44, 95% CI 1.04-2.01), the overall rate of hospital admissions was significantly increased for valproate compared with lithium., Conclusions: In daily clinical practice, treatment with lithium seems in general to be superior to treatment with valproate.

Objective: To investigate whether treatment with lithium in patients with mania or bipolar disorder is associated with a decreased rate of subsequent dementia., Methods: Linkage of register data on prescribed lithium in all patients discharged from psychiatric health care service with a diagnosis of mania or bipolar disorder and subsequent diagnoses of dementia in Denmark during a period from 1995 to 2005., Results: A total of 4,856 patients with a diagnosis of a manic or mixed episode or bipolar disorder at their first psychiatric contact were included in the study. Among these patients, 2,449 were exposed to lithium (50.4%), 1,781 to anticonvulsants (36.7%), 4,280 to antidepressants (88.1%), and 3,901 to antipsychotics (80.3%) during the study period. A total of 216 patients received a diagnosis of dementia during follow-up (103.6/10,000 person-years). During the period following the second prescription of lithium, the rate of dementia was decreased compared to the period following the first prescription. In contrast, the rates of dementia during multiple prescription periods with anticonvulsants, antidepressants, or antipsychotics, respectively, were not significantly decreased compared to the rate of dementia during the period with one prescription of these drugs., Conclusions: Continued treatment with lithium was associated with a reduced rate of dementia in patients with bipolar disorder in contrast to continued treatment with anticonvulsants, antidepressants, or antipsychotics. Methodological reasons for these findings cannot be excluded due to the nonrandomized nature of the data.

Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross-sectional high-risk study. Healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Awakening and evening salivary cortisol levels were compared between the 190 High- and Low-Risk twins. The 109 High-Risk twins had significantly higher evening cortisol levels than the 81 Low-Risk MZ twins, also after adjustment for age, sex, and the level of subclinical depressive symptoms. No significant difference was found in awakening cortisol levels between High-Risk and Low-Risk twins. In conclusion, a high genetic liability to affective disorder was associated with a higher evening cortisol level, but not with awakening cortisol level. Future prospective family, high-risk and twin studies are needed to decide whether abnormalities in the HPA axis can be identified as an endophenotype of affective disorder.

Context: It has been suggested that lithium may have neuroprotective abilities, but it is not clear whether lithium reduces the risk of dementia., Objective: To investigate whether continued treatment with lithium reduces the risk of dementia in a nationwide study., Design: An observational cohort study with linkage of registers of all patients prescribed lithium and diagnosed as having dementia in Denmark from January 1, 1995, through December 31, 2005., Setting: We identified all patients treated with lithium in Denmark within community psychiatry, private specialist, and general practices and a random sample of 30% of the general population. Subjects A total of 16,238 persons who purchased lithium at least once and 1,487,177 persons from the general population who did not purchase lithium. Main Outcome Measure Diagnosis of dementia or Alzheimer disease during inpatient or outpatient hospital care., Results: Persons who purchased lithium at least once had an increased rate of dementia compared with persons not exposed to lithium (relative risk, 1.47; 95% confidence interval, 1.22-1.76). For persons who continued to take lithium, the rate of dementia decreased to the same level as the rate for the general population. The rate of dementia decreased early after the consumption of lithium tablets corresponding to 1 prescription (typically 100 tablets) and stayed at a low level, although with a slight increase according to the number of subsequent prescriptions. The association between the number of prescriptions for lithium and dementia was unique and different from the association between the number of prescriptions for anticonvulsants and dementia. All findings were replicated in subanalyses with Alzheimer disease as the outcome., Conclusions: Continued lithium treatment was associated with reduction of the rate of dementia to the same level as that for the general population. Methodological reasons for this finding cannot be excluded, owing to the nonrandomized nature of data.

Objectives: This study investigated the association between continued mood-stabilizing treatment (lithium and anticonvulsants) in bipolar disorder (BD) and the risk of suicide., Methods: Using linkage of national registers, the association between continued mood-stabilizing treatment and suicide was investigated among all patients discharged nationwide from hospital psychiatry as an in- or outpatient in a period from 1995 to 2000 in Denmark with a diagnosis of BD., Results: A total of 5,926 patients were included in the study and among these 51 patients committed suicide eventually during the study period. Although the rate of suicide was higher during periods when patients purchased anticonvulsants (293 suicides per 100,000 person-years) than during periods with lithium (136 suicides per 100,000 person-years), the suicide rate decreased with the number of prescriptions in a rather similar way for patients first treated with lithium and patients first treated with anticonvulsants: patients who continued treatment with mood-stabilizing drugs had a decreased rate of suicide compared to patients who purchased mood stabilizers once only [rate ratio for anticonvulsants = 0.28, 95% confidence interval (CI) = 0.19-0.41; rate ratio for lithium = 0.20, 95% CI = 0.10-0.38]. Further, the rate of suicide decreased consistently with the number of additional prescriptions. Switch to or augmentation with lithium to patients initiated on anticonvulsants was associated with a significantly reduced rate of suicide (rate ratio = 0.28, 95% CI = 0.20-0.40), whereas a switch to or augmentation with anticonvulsants to patients first started on lithium showed no additional effect on the suicide rate., Conclusions: Although continued treatment with anticonvulsants and continued treatment with lithium was associated with a rather similar reduction in the rate of suicide, the results suggest that treatment with lithium may have some superiority in relation to prevention of suicide.

Findings from several studies have suggested that the risk of recurrence increases with the number of previous episodes in depressive and bipolar disorders. However, a comprehensive and critical review of the literature published during the past century shows that in several previous studies, a progressive course of episodes may have been falsely shown, mainly because of various kinds of biases and because these studies have not considered individual heterogeneity in their analyses. Nevertheless, four recent studies, including two nationwide register studies from Denmark, a prospective 15-year multicenter study from the United States, and a prospective lifelong study from Zurich, Switzerland, generally have taken these drawbacks and pitfalls into account in the design and handling of data. In all four studies, an effect of episodes was found in depressive (four studies) and bipolar (three studies) disorders. It is concluded that the average risk of recurrence increases with the number of episodes in depressive and in bipolar affective disorders. Nevertheless, the course of illness in unipolar and bipolar disorders is heterogeneous, and the effect of previous episodes and its interrelation with other risk factors on the risk of relapse and recurrence warrants additional research.

Objective: Several findings suggest that some patients with depressive or bipolar disorder may be at increased risk of developing dementia. The present study aimed to investigate whether the risk of developing dementia increases with the number of affective episodes in patients with depressive disorder and in patients with bipolar disorder., Methods: This was a case register study including all hospital admissions with primary affective disorder in Denmark during 1970-99. The effect of the number of prior episodes leading to admission on the rate of readmission with a diagnosis of dementia following the first discharge after 1985 was estimated. A total of 18,726 patients with depressive disorder and 4248 patients with bipolar disorder were included in the study., Results: The rate of a diagnosis of dementia on readmission was significantly related to the number of prior affective episodes leading to admission. On average, the rate of dementia tended to increase 13% with every episode leading to admission for patients with depressive disorder and 6% with every episode leading to admission for patients with bipolar disorder, when adjusted for differences in age and sex., Conclusion: On average, the risk of dementia seems to increase with the number of episodes in depressive and bipolar affective disorders.

Background: Newer antidepressants have increasingly been used during the past decade. These drugs may increase compliance and reduce the risk of cycle acceleration in affective disorders., Aims: To investigate the naturalistic longitudinal course of illness in patients with depressive or bipolar disorder following the use of recently introduced drugs., Method: The rates of relapse leading to hospitalisation after successive episodes were calculated in a case register study including all hospital admissions of patients with primary affective disorder in Denmark during 1994-1999. Altogether, 9417 patients had a diagnosis of depressive disorder and 1106 patients had a diagnosis of mania or bipolar disorder, at first-ever discharge., Results: The rate of relapse leading to hospitalisation increased with the number of previous episodes in both depressive and bipolar disorders. However, the effect of episodes was not significant for men. The rate of relapse did not decline during the study period., Conclusions: The course of severe depressive and bipolar disorders has remained roughly the same despite introduction of new treatments.

A few studies have suggested that the prevalence of diabetes is increased for patients with depression and for patients with bipolar disorder compared with the general population. However, no study has been published comparing the risk of getting a diagnosis of diabetes for patients with affective disorders with the risk for patients with other medical illnesses. It was the aim of the present study to investigate whether patients hospitalised for depressive or bipolar disorders are at increased risk of getting a diagnosis of diabetes at readmission compared to patients previously admitted for osteoarthritis. In a nationwide case register study, all patients who got a discharge diagnosis of depression, mania/bipolar disorder or osteoarthritis at first admission in a period from 1977 to 1997 were identified. The probability of getting readmitted and discharged with a diagnosis of diabetes was estimated with competing risks models in survival analysis. In total, 29,035 patients with a diagnosis of depression at first discharge, 6683 patients with mania/mixed episode and 108,525 patients with a diagnosis of osteoarthritis were identified. The risk of getting readmitted with diabetes was not increased for patients who had previously been admitted with depression or mania/bipolar disorder compared to patients with osteoarthritis. There was no difference in the risks of developing Type 1 and Type 2 diabetes.

Objective: It is generally accepted that one of the most important predictors of recurrence in depressive and bipolar disorders is the number of previous episodes. However, very few studies have considered the individual tendency toward recurrence in analyses of the effect of the number of episodes on the risk of subsequent recurrence in affective disorder., Method: Frailty models were used to estimate the effect of the number of episodes on the rate of recurrence taking into account the individual frailty toward recurrence. The study base consisted of 406 patients, 186 patients with depressive disorder and 220 patients with bipolar disorder, who were admitted between 1959 and 1963 to the Psychiatric Hospital University of Zurich with an affective episode and followed up to 1997., Results: The individual rate of subsequent recurrence was found to increase with the number of episodes even when the effect was adjusted for the individual frailty toward recurrence. The effect of episodes was the same in depressive and bipolar disorders and for men and women., Conclusion: It seems increasingly valid that in depressive and bipolar disorders, the risk of subsequent recurrence increases with the number of episodes.

Objective: To investigate the time relation between dementia and major affective disorders (major depression and mania)., Methods: Register linkage study of the Danish Hospital Register and the Danish Psychiatric Central Research Register, to establish study cohorts of patients with dementia and control groups (osteoarthritis or diabetes) on first discharge from hospital. Follow up of cohorts was for up to 21 years. Hazard of death was allowed for by the use of competing risks models., Results: Patients with dementia had an increased risk of being admitted to hospital for major depression or mania during the course of the illness. The incidence remained elevated throughout the rest of the patient's life., Conclusions: Patients with dementia have an increased risk of developing depression or mania. Proper treatment of affective disorders in patients with dementia is important in reducing suffering and costs.

Background: The risk of recurrence has been found to increase with the number of episodes in both unipolar and bipolar affective disorder. The present study compared the effect of the number of episodes on the risk of recurrence in the two disorders., Method: A case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. The effect of the number of prior episodes on the rate of recurrence following the first discharge after 1984 was estimated. A total of 7925 unipolar patients and 2011 bipolar patients were included in the study., Results: The rate of recurrence was, on average, 1.6 times greater for bipolar patients than for unipolar patients. Nevertheless, the effect of the number of episodes was greatest for unipolar patients. Thus, the rate of recurrence increased, on average, 15% with every episode for unipolar patients and 9% with every episode for bipolar patients, when adjusted for differences in age and gender., Conclusion: The risk of recurrence increases with every new episode in affective disorder. The effect of episodes is greater for unipolar disorder than for bipolar disorder., Limitations: The data relate to re-admissions rather than recurrence., Clinical Relevance: The study shows that the prognosis worsens more for unipolar than for bipolar patients with each new episode and suggests the relevance of earlier and more sustained intervention.

In recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results. Survival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. Totally, 20,350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/circular type. The rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders. The course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.