[German S3 guidelines on bipolar disorders-first update 2019 : What is new in pharmacotherapy?] / S3-Leitlinie Bipolare Störungen ­ 1. Update 2019 : Was ist neu in der Pharmakotherapie?

BACKGROUND: German S3 guidelines are subject to the highest methodological standards. This includes that they are only valid for a certain time period. Following the first edition in 2012 the first update of the S3 guidelines on bipolar disorder has now been published (2019). OBJECTIVE: What has changed in the field of pharmacological recommendations comparing the first edition with the update in 2019? MATERIAL AND METHODS: Comparison of the 1st edition from 2012 with the update from 2019 of the S3 guidelines for the diagnostics and treatment of bipolar disorders. RESULTS: The three principle treatment targets of acute treatment of bipolar depression, acute treatment of mania and phase prophylaxis (maintenance treatment) can be distinguished. For acute treatment of bipolar depression, for the first time a medication has received a level A recommendation: quetiapine. For the acute treatment of mania, several drugs are still recommended with the same level of recommendation (B). Asenapine has been added as the tenth substance. Lithium is still the only drug with a level A recommendation for maintenance and prophylactic treatment and is also the only drug approved for this indication without restrictions. A new recommendation is that in the absence of contraindications, phase prophylaxis with a serum level of at least 0.6 mmol/l should be carried out. With a B recommendation, quetiapine has been added to the drugs for phase prophylactic treatment. CONCLUSION: The S3 guidelines make recommendations at the highest scientific level. In view of these findings, lithium is clearly underutilized for maintenance therapy. In the absence of clear contraindications (advanced renal insufficiency), every patient with bipolar disease should be given the chance of lithium prophylaxis for an adequately long period.

Are national suicide prevention programs effective? A comparison of 4 verum and 4 control countries over 30 years.

BACKGROUND: Suicide and non-fatal suicidal behavior are significant public health issues worldwide requiring effective preventive interventions. METHODS: The aim of the present study was to analyze the effectiveness of national suicide prevention programs taking a statistical approach involving the segmented regression analysis of interrupted time series data. RESULTS: This study demonstrates that National Suicide Prevention Programs are effective, but this effect seems to correlate with age and sex. Our data have shown a statistical significant decline in suicide rates in the verum countries in males, with the strongest effects in groups aged 25-to-44 years and 45-to-64 years. CONCLUSION: Our study implies that the implementation of a national strategy is an effective tool to reduce suicide rates.

[Correct treatment of mood disorders with lithium]. / Sachgerechte Behandlung affektiver Störungen mit Lithium.

Due to their unique therapeutic effects and high efficacy, lithium salts are recommended in guidelines, particularly for the treatment of mood disorders; however, despite the therapeutic efficacy lithium treatment is underutilized in the treatment of these disorders. The therapeutic efficacy of lithium is contrasted by a narrow therapeutic range and a potential risk of intoxication, which is why close drug monitoring is necessary during lithium treatment. Furthermore, lithium therapy requires well-founded knowledge about patient selection with respect to approved areas of administration and indications. This review article summarizes clinically relevant knowledge of lithium treatment to improve treatment of patients with mood disorders and to increase patient safety when using lithium.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

[Suicidal ideation of prisoners : Influence of duration of imprisonment, personality traits and disorders]. / Suizidalität von Inhaftierten : Einfluss von Haftdauer, Persönlichkeitsauffälligkeiten und Persönlichkeitsstörungen.

BACKGROUND: Although in recent years many efforts have been made in suicide prevention, suicidal ideation in prison is still a major problem. The present study is part of a project being carried out in Saxony, Germany on the investigation and prevention of suicide in prisons. OBJECTIVE: The aim of this study was to determine whether the duration of imprisonment, personality traits and personality disorders have an influence on the suicidal ideation of prisoners. MATERIAL AND METHODS: In this study 113 volunteers among prisoners from 6 prisons in Saxony participated in a structured interview and filled out several questionnaires on sociodemographic details, personality using the personality style and disorder inventory (PSSI) and the assessment of DSM-IV personality disorders (ADP-IV) questionnaire as well as attitudes towards suicide using the questionnaire on stressful social experiences (FBS) and the Viennese instrument for suicidality on correctional institutions (VISCI). RESULTS: Significant correlations were found between personality traits and personality disorders and suicidal ideation and suicide attempts. A positive correlation was also found between personality disorders and scores in the VISCI. High scores in the PSSI were correlated with all aspects of suicidal ideation; however, length of time spent in prison and total duration of imprisonment appeared to have little impact on suicide parameters and were only correlated with the self-declared current suicidal ideation. DISCUSSION: Although there were some limitations, this study could confirm data in the literature that personality disorders are associated with an increased risk of suicidal ideation in prisoners. The lack of association of suicidal thoughts as measured in this study with the total time spent in prison and duration of imprisonment is in contradiction to the results of other studies and warrants further investigation.

[Psychopharmaceuticals for treatment of suicidal patients and for suicide prevention]. / Psychopharmaka zur Behandlung suizidaler Patienten und zur Suizidprävention.

Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term "suicidality" seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided.

Treatment of lithium intoxication: facing the need for evidence.

Lithium has been used as the gold standard in the treatment of major depressive and bipolar disorders for decades. Due to its narrow therapeutic index, lithium toxicity is a common clinical problem. Although risk factors for lithium intoxication seem to be well-described, lacking patient education and inexperience of treatment are assumed to contribute to the probability of lithium intoxication. A review of literature shows that the treatment of lithium intoxication has not been adequately studied or standardized. The aim of this literature review is to compile and present current evidence on the treatment of lithium intoxication and contribute to a standardization regarding general treatment recommendations as well as evidence on indication for extracorporeal methods. Against the background of this common and potentially life-threatening condition, the standardization of the treatment of lithium intoxication is definitely a task for the future.

[Is there an increased risk for renal tumors during long-term treatment with lithium?]. / Gibt es bei der Lithiumlangzeitbehandlung ein erhöhtes Risiko für Nierentumoren?

Lithium salts are the recommended first-line treatment (gold standard) in national and international treatment guidelines for acute and maintenance treatment of affective disorders, such as bipolar disorders. Lithium has also been shown to have a unique protective effect against suicide in patients suffering from affective disorders. Despite the well-known acute and long-term adverse effects lithium therapy can be safely administered if patients are properly educated and carefully monitored. A recent study from France now shows that patients with severely impaired renal function who had been treated with lithium salts for more than 10 years could have an increased risk for kidney tumors (benign and malignant). This resulted in an adjustment concerning information within the package leaflet by European authorities. The authors of this article reflect the currently available data in order to better understand and handle this new finding and to warn about uncritical reactions including withdrawal of lithium in successfully treated patients. This article provides clinical recommendations to provide further insight relating to the risk of kidney cancer in long-term lithium therapy.

The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review.

The management and treatment of patients with suicidal behavior is one of the most challenging tasks for health-care professionals. Patients with affective disorders are at high risk for suicidal behavior, therefore, should be a target for prevention. Numerous international studies of lithium use have documented anti-suicidal effects since the 1970s. Despite the unambiguous evidence of lithium's anti-suicidal effects and recommendations in national and international guidelines for its use in acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a comprehensive review of studies investigating the anti-suicidal effect of lithium in patients with affective disorders.

Does lithium reduce acute suicidal ideation and behavior? A protocol for a randomized, placebo-controlled multicenter trial of lithium plus Treatment As Usual (TAU) in patients with suicidal major depressive episode.

BACKGROUND: Lithium has proven suicide preventing effects in the long-term treatment of patients with affective disorders. Clinical evidence from case reports indicate that this effect may occur early on at the beginning of lithium treatment. The impact of lithium treatment on acute suicidal thoughts and/or behavior has not been systematically studied in a controlled trial. The primary objective of this confirmatory study is to determine the association between lithium therapy and acute suicidal ideation and/or suicidal behavior in inpatients with a major depressive episode (MDE, unipolar and bipolar disorder according to DSM IV criteria). The specific aim is to test the hypothesis that lithium plus treatment as usual (TAU), compared to placebo plus TAU, results in a significantly greater decrease in suicidal ideation and/or behavior over 5 weeks in inpatients with MDE. METHODS/DESIGN: We initiated a randomized, placebo-controlled multicenter trial. Patients with the diagnosis of a moderate to severe depressive episode and suicidal thoughts and/or suicidal behavior measured with the Sheehan-Suicidality-Tracking Scale (S-STS) will be randomly allocated to add lithium or placebo to their treatment as usual. Change in the clinician administered S-STS from the initial to the final visit will be the primary outcome. DISCUSSION: There is an urgent need to identify treatments that will acutely decrease suicidal ideation and/or suicidal behavior. The results of this study will demonstrate whether lithium reduces suicidal ideation and behavior within the first 5 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02039479.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Influence of levothyroxine in augmentation therapy for bipolar depression on central serotonergic function.

INTRODUCTION: Adjunctive treatment with supraphysiological doses of levothyroxine (L-T4) in bipolar depression shows promise, but the neurobiological mechanisms underlying clinical improvement are unknown. It has been postulated from animal studies that exogenous thyroid hormones may exert their modulatory effects in patients with affective disorders via an increase in serotonergic neurotransmission. Therefore, we investigated the loudness dependence of auditory evoked potentials (LDAEP) as a measure of central serotonergic activity and response to L-T4. METHODS: This 6-week, double-blind, randomized, placebo-controlled study assessed the efficacy of L-T4 adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication in 20 patients with bipolar depression. LDAEP was assessed before and after treatment with L-T4. RESULTS: Scores of the Hamilton Depression Rating Scale and Montgomery Asberg Depression Rating Scale decreased significantly during the study. There was no difference in pre- and post-treatment LDAEP between the groups, and no correlation between LDAEP and psychometric measures in the course of the study. DISCUSSION: The hypothesis of a relationship between response of augmentation therapy with levothyroxine in bipolar depression and serotonergic activity could not be confirmed.

Regularity in daily mood stabilizer dosage taken by patients with bipolar disorder.

OBJECTIVE: The aim of this study was to investigate regularity in the daily mood stabilizer dosage taken by patients with bipolar disorder, and identify factors associated with irregularity. METHODS: Self-reported daily mood and medication data were available from 206 patients who took the same mood stabilizer for ≥100 days. Approximate entropy (ApEn) was used to measure serial regularity in daily mood stabilizer dosage. Generalized estimating equations (GEE) were used to estimate if demographic or clinical variables were associated with ApEn. RESULTS: There was a wide range of regularity in the daily mood stabilizer dosage. The mean percent of days of missing doses was 13.6%. The number of psychotropic medications (p=0.007), pill burden (p=0.004) and percent of days with depressed mood (p=0.013) were associated with more irregularity, while the percent of days euthymic (p=0.014) was associated with less irregularity. The percent of days missing doses was not associated with the number of medications, pill burden or mood ratings. DISCUSSION: Patients may have irregularity in daily dosage in spite of a low percent of days missing doses. Psychotropic medication regimen complexity and depression are associated with increased dosage irregularity. Research is needed on how irregularity in daily dosage impacts the continuity of drug action of mood stabilizers.

[Anti-suicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders]. / Suizidprophylaktische Wirkung von Lithium : Aktueller Forschungsstand und Implikationen für die Therapie affektiver Störungen.

Treatment of patients with suicidal behaviour is one of the most challenging tasks for health care professionals. Due to the high mortality, morbidity and costs related to suicide, the development of treatment and preventive strategies for suicidal behaviour have been a focus of psychiatric research. For lithium, one of the oldest pharmacological agents used in psychiatry, anti-suicidal effects have been found since the early 90s in many international studies. Despite this unambiguous evidence and corresponding recommendations in national and international guidelines for the acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a review of studies investigating the anti-suicidal effects of lithium in affective disorders. Clinical implications for the treatment of affective disorders are discussed.

The relationship of Akathisia with treatment emergent suicidality among patients with first-episode schizophrenia treated with haloperidol or risperidone.

Akathisia as well as younger age, early illness onset and discharge are important risk factors for suicidality in patients with first-episode schizophrenia. The aim of the present study was to analyze on a single case basis the relationship between a sudden increase in suicidality, anxiety symptoms, medication dosing and clinician- and patient-rated akathisia. A small subsample of patients demonstrated a positive relationship between suicidality and akathisia scores within the titration period of the study medication.

No correlation between lithium serum levels and psychopathological features during the euthymic interval of patients with recurrent affective disorder.

INTRODUCTION: The aim of this prospective study was to investigate the influence of lithium serum levels on subclinical psychopathological features during the euthymic interval in patients with an affective disorder. METHODS: The study included 54 patients with a recurrent affective disorder undergoing a continuous prophylactic lithium treatment (31 unipolar, 23 bipolar). The observation period lasted for 2 years and included 332 visits. Visits consisted of a detailed interview, a continuous measurement of lithium levels and the collection of validated scales including HAMD, YMRS, CGI, VAMS and the SCL-90R. Several correlations between lithium serum levels and different psychopathological features during the euthymic interval were calculated on an individual patient basis and on a group basis to reveal generally occurring correlations. RESULTS: No generally occurring significant correlations between lithium serum levels and specific psychopathological features were found. Only on a single patient level, 32 significant correlations between lithium level and specific psychopathological features were found, partly indicating a negative and partly indicating a positive influence of higher lithium levels on psychopathological symptoms. Nevertheless, in the group analyses no significant correlations were found. DISCUSSION: Higher lithium levels were not associated with an improved psychopathological status, but they were not associated with a worse status (due to a higher burden of side effects) either. According to the literature there is currently no strong evidence to treat patients with a higher lithium level. It is recommended to start with a lower level and to continue with individual adjustments in accordance to prophylactic efficacy and tolerability.

Comparison of pre-episode and pre-remission states using mood ratings from patients with bipolar disorder.

Daily self-reported mood ratings from patients with bipolar disorder were analyzed to see if the 60 days before an episode of hypomania or depression (pre-episode state) could be distinguished from the 60 days before a month of euthymia (pre-remission state), and if a pre-hypomanic state could be distinguished from a pre-depressed state. Data were available from 98 outpatients with bipolar disorder, who returned about one year of daily data, and received treatment as usual. The approximate entropy (ApEn), mean mood and mood variability (standard deviation) were determined for 53 pre-hypomanic states, 42 pre-depressive states, and 65 pre-remission states.There was greater serial irregularity (ApEn) and greater variability in mood in the pre-episode than the pre-remission state. There was greater serial irregularity (ApEn) but no difference in variability in mood in the pre-hypomanic state when compared to the pre-depressed state. ApEn can distinguish between the pre-episode, pre-remission, pre-hypomanic and pre-depressive states. Using daily mood ratings, pre-episode changes were detected before the episode onset. Further investigation to relate the pre-episode and pre-remission states to other clinical and biological data is indicated.