[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.

[Ambulatory monitoring and digital phenotyping in the diagnostics and treatment of bipolar disorders]. / Ambulantes Monitoring und digitale Phänotypisierung in Diagnostik und Therapie bipolarer Erkrankungen.

BACKGROUND: Reliable and valid diagnostics and treatment of bipolar disorders and affective episodes are subject to extensive, especially methodological limitations in the clinical practice. OBJECTIVE: The use of smartphones and mobile sensor technology for improvement in diagnostics and treatment of bipolar disorders. METHODS: Critical discussion of current research on the use of ambulatory monitoring and digital phenotyping with bipolar disorders. RESULTS: In many studies the observation periods were too short and the sensors applied were too inaccurate to enable reliable and valid detection of behavioral changes in the context of affective episodes. CONCLUSION: The clarification and operationalization of psychopathological constructs to allow for the measurement of objectively observable and ascertainable behavioral changes during depressive and (hypo)manic states are essential for the successful application of modern mobile technologies in the diagnostics and treatment of bipolar disorders.

[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.

[Guideline-adherent psychiatric psychotherapeutic treatment of bipolar disorders : Which resources are needed?] / Leitliniengerechte psychiatrisch-psychotherapeutische Behandlung bei bipolaren Störungen : Welche Ressourcen werden dafür benötigt?

In this article the guideline-adherent psychiatric psychotherapeutic treatment of patients with bipolar disorders is outlined and the required resources are estimated. Based on the core recommendations of the S3 guidelines for diagnostics and treatment of bipolar disorders published in 2012, inpatient treatment needs in hours per week and per patient are determined for both manic and bipolar depressive episodes. The resulting staffing requirements are estimated on this basis. In summary, for guideline-adherent inpatient psychiatric psychotherapeutic treatment the additional needs regarding the physician/psychotherapeutic domain add up to 44 min per patient and week during a manic episode and 88 min for patients with bipolar depression when compared to current psychiatry staffing regulations.

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.

[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.

[Bipolar disorders in DSM-5]. / Bipolare Störungen im DSM-5.

BACKGROUND: In spring 2013 the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) edited by the American Psychiatric Association was published. The DSM-5 has also brought some important changes regarding bipolar disorders. OBJECTIVES: The goal of this manuscript is to review the novelties in DSM-5 and to evaluate the implications of these changes. MATERIALS AND METHODS: The diagnostic criteria as well as the additional remarks provided in the running text of DSM-5 were carefully appraised. RESULTS: For the first time diagnostic criteria are provided for disorders which up to now have been considered as subthreshold bipolar disorders. Furthermore, mixed episodes were eliminated and instead a mixed specifier was introduced. An increase in goal-directed activity/energy is now one of the obligatory symptoms for a (hypo)manic episode. Diagnostic guidance is provided as to when a (hypo)manic episode that has developed during treatment with an antidepressant has to be judged to be causally related to antidepressants and when this episode has only occurred coincidentally with antidepressant use. CONCLUSIONS: While some of the novelties are clearly useful, e.g. addition of increased goal-directed activity/energy as obligatory symptom for (hypo)manic episodes, this remains to be demonstrated for others, such as the definition of various subthreshold bipolar disorders.

[Prevention of bipolar disorders]. / Prävention bipolarer Störungen.

In the past, preventive measures for psychoses have focused mainly on schizophrenic disorders. Bipolar disorders are often diagnosed and treated with a significant delay. The expansion of preventive measures for bipolar disorders aims at minimizing the substantial negative consequences associated with the disease. Some of the shared aspects of prevention in psychoses and bipolar disorders are that the first symptoms commonly appear during adolescence and early adulthood and that there is a symptomatic overlap between the disorders. To improve efforts to seek early help, public information about mental illness, low threshold services as well as cooperation between adult, child and adolescent psychiatry are needed for this target group. One differences is that psychotic symptoms play a minor role in bipolar disorders. Specific biological markers, such as disturbances of sleep and circadian rhythm and clinical characteristics, such as substance use and behavioral problems in childhood and youth supplement (subsyndromal) clinical symptoms in a multifactorial risk model. Besides severity and frequency of symptoms, specific periodic course patterns are crucial. Strategies of early intervention require a careful consideration of risks and benefits. Two aims should be distinguished: the improvement of current symptomatology and the prevention of conversion to bipolar disorder. Currently, studies evaluating risks and benefits of such interventions are first conducted. Expertise and resources for early recognition of psychoses and bipolar disorders should be pooled. Common standards are the basis for advancement and implementation of preventive strategies for bipolar disorders.

[The challenge of treating bipolar outpatients]. / Herausforderungen der ambulanten Behandlung von Patienten mit bipolar-affektiven Störungen.

The course of bipolar illness comprises a wide range, which may vary between one single episode once every five years and a severe ultra rapid cycling course with mood changes within days. Even with optimal pharmacological treatment the functional outcome in bipolar patients is still poor. Underlying pathomechanisms are not fully understood yet. This article addresses three possible illness specific-aspects: cognitive defects, high relapse frequency and poor adherence. Causes as well as therapeutic interventions for these therapeutic pitfalls are summarised.

[Mirtazapine and hyperemesis gravidarum]. / Mirtazapin bei Hyperemesis gravidarum.

The case of a 29-year-old patient in the 21st gestational week with severe hyperemesis gravidarum which did not respond to conventional antiemetic treatment is reported. Nausea and vomiting improved within 48 h after i.v. administration of 30 mg mirtazapine/day. The pathophysiological and therapeutic implications are discussed.

Effect of aripiprazole on cognition in the treatment of patients with schizophrenia.

BACKGROUND: The aim of this study was to assess the cognitive effects of aripiprazole in inpatients with schizophrenia. METHODS: This was an investigator-initiated, open label eight-week trial evaluating 56 inpatients with the DSM-IV diagnosis of schizophrenia. Efficacy was assessed weekly using the Positive and Negative Syndrome Scale (PANSS) and tolerability was assessed each week using the Udvalg for Klinske Undersogelser side effect rating scale (UKU). Cognitive function was assessed at baseline, week 4 and week 8. RESULTS: Aripiprazole showed significant improvement in PANSS total score and all subscores between baseline and endpoint visit. The substance was very well tolerated. Patients improved significantly in verbal memory, reaction time and reaction quality/attention from baseline to week eight. Furthermore, mean z-values of individual cognitive domains summarized in a global cognitive index improved significantly from baseline to week eight. DISCUSSION: Our results suggest that aripiprazole provides a valuable treatment option for patients with schizophrenia.

[Bipolar depression. Spectrum of clinical pictures and differentiation from unipolar depression]. / Bipolare Depression. Spektrum klinischer Erscheinungsbilder und Abgrenzbarkeit von der unipolaren Depression.

Patients with bipolar disorder often present initially with a major depressive episode. The correct diagnosis at the first presentation could help to find an effective medication regimen, to prevent antidepressant-induced rapid cycling and to reduce antidepressant-induced manic episodes, e.g. though combination therapy with a mood stabilizer. Consistent predictors for an underlying bipolar illness are an early age of onset, a highly recurrent illness course with more than five episodes, the presentation of atypical features, psychotic symptoms, the presence of psychiatric comorbidities like anxiety disorders, history of suicide attempts (especially at an early age), positive family anamnesis for bipolar disorder, and a rapid evolvement of the depressive episode. So far there are no pathognomonic markers for bipolar disorder. Therefore we propose to assess the risk of each patient for having bipolar disorder individually. Patients who are at a high risk should at least be informed and should be closely monitored for the development of manic episodes.

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.

Heart rate variability and Omega-3 Index in euthymic patients with bipolar disorders.

BACKGROUND: Affective disorders are associated with an increased risk of cardiovascular disease, which, at least partly, appears to be independent of psychopharmacological treatments used to manage these disorders. Reduced heart rate variability (SDNN) and a low Omega-3 Index have been shown to be associated with increased risk for death after myocardial infarction. Therefore, we set out to investigate heart rate variability and the Omega-3 Index in euthymic patients with bipolar disorders. METHODS: We assessed heart rate variability (SDNN) and the Omega-3 Index in 90 euthymic, mostly medicated patients with bipolar disorders (Bipolar-I, Bipolar-II) on stable psychotropic medication, free of significant medical comorbidity and in 62 healthy controls. Heart rate variability was measured from electrocardiography under a standardized 30 minutes resting state condition. Age, sex, BMI, smoking, alcohol consumption and caffeine consumption as potential confounders were also assessed. RESULTS: Heart rate variability (SDNN) was significantly lower in patients with bipolar disorders compared to healthy controls (35.4 msec versus 60.7 msec; P<0.0001), whereas the Omega-3 Index did not differ significantly between the groups (5.2% versus 5.3%). In a linear regression model, only group membership (patients with bipolar disorders versus healthy controls) and age significantly predicted heart rate variability (SDNN). CONCLUSION: Heart rate variability (SDNN) may provide a useful tool to study the impact of interventions aimed at reducing the increased risk of cardiovascular disease in euthymic patients with bipolar disorders. The difference in SDNN between cases and controls cannot be explained by a difference in the Omega-3 Index.

Association of cognitive deficits with elevated homocysteine levels in euthymic bipolar patients and its impact on psychosocial functioning: preliminary results.

OBJECTIVES: Elevated homocysteine (Hcy) levels have been demonstrated to have a negative impact on cognitive functioning in healthy elderly people. Further studies suggest that they are an independent risk factor for dementia, in particular for Alzheimer's disease. Bipolar disorder is also associated with cognitive impairment. However, the pathophysiological mechanisms of these deficits have not been elucidated yet. This study examines the role of Hcy on cognition and its impact on psychosocial functioning in euthymic bipolar patients. METHODS: A total of 55 euthymic bipolar patients and 17 healthy controls were enrolled in the study. Neuropsychological assessments consisted of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Trail Making Test (TMT), the Weschler Adult Intelligence Scale, 3(rd) edition (WAIS-III) subtest Letter-Number Sequencing Test (LNST) and the HAWIE-R (German version of the WAIS-R) subtest Information. Psychosocial functioning was assessed using the Social Adjustment Scale (SAS). To obtain plasma levels of Hcy, blood samples were collected in EDTA tubes, immediately put on ice, centrifuged within 15 min and stored at -80 degrees C. Total Hcy concentration was measured using high-performance liquid chromatography. RESULTS: In the neuropsychological tests, patients differed significantly from healthy controls on the TMT B and the RBANS composite indices Language, Attention and Total Score. No differences were found on the HAWIE-R subtest Information, the TMT A, LNST or the RBANS composite indices Immediate Memory, Visuospatial/Constructional Abilities and Delayed Memory. Mean Hcy levels were 9.8 +/- 3.2 microm/L in the patient group and 7.8 +/- 2.1 microm/L in the control group, respectively (p = 0.012). In the patient group Hcy levels significantly correlated with gender, diagnosis and RBANS index scores for Immediate Memory, Language, Attention and Total Score. Linear regression analyses revealed a significant and independent association of Hcy levels with Immediate Memory and TMT B scores in the patient group. Homocysteine levels did not correlate with any measure in the control group. Spearman's correlations indicated that psychosocial functioning in bipolar patients is not associated with clinical variables apart from time in remission. However, it correlated significantly with working memory measures (LNST). No relationship could be determined between psychosocial functioning and Hcy plasma levels. CONCLUSIONS: Elevated Hcy levels seem to be associated with cognitive impairment in euthymic bipolar patients, but not with psychosocial functioning. More studies are needed to clarify the role of Hcy in cognition in bipolar disorder.

[Agoraphobia and "psychogenic"-attributed gait disorder as symptoms of "stiff-man" syndrome]. / Agoraphobie und "psychogen" anmutende Gangstörung als Symptome eines "stiff-man"-Syndroms (SMS).

We report on two patients with truncal rigidity and agoraphobia. The fear of crossing open places had been judged as psychogenic in both cases. The detection of positive GAD-antibodies led to our final diagnosis. Treatment with liquorphoresis and clonazepam or diazepam alone resulted in a prompt amelioration of the rigidity and, to a lesser extent, of the agoraphobia as well. The stiff-man syndrome has neurological and psychological aspects and shows one more facet of the syndrome of agoraphobia first described by Westphal.

Activated Borna disease virus in affective disorders.

BACKGROUND: Borna disease virus (BDV) is an animal pathogen that causes behavioral changes in animals. Previous studies have found a high prevalence of serum antibodies as well as Borna disease viral antigens (BDVAGs) and RNA in the white blood cells of psychiatric patients, especially those with affective disorders. The present study attempts to offer a better description of the BDVAG cohort using clinical parameters. METHODS: The prevalence of BDVAG was examined in the peripheral mononuclear leukocytes of patients with a major depressive episode. A subgroup of patients underwent further clinical analysis. RESULTS: In this pilot study, at least, there was a significant difference in the prevalence of BDVAG between psychiatric inpatients with a major depressive episode and control individuals. It also appeared that BDVAG is more frequent in patients with recurrent major depression or bipolar disorder than in those with any other psychiatric disorder studied. The number of previous depressive episodes, as well as symptoms involving fatigue and concentration difficulties were positively related to BDVAG. CONCLUSIONS: The high rate of BDVAG, especially in fatigued patients with recurrent major depression or bipolar disorder, may be a nonspecific aspect of immunosuppression. The question remains whether this neurotropic virus may contribute to the pathogenesis of some types of affective disorder.

Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection.

Amantadinesulfate is a well known substance which has proven useful in the treatment and prophylaxis of viral infections, in treating symptoms of Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It has also been reported as having mild antidepressive effects not sufficient to warrant its use as an antidepressant. Striking antidepressive effects in some patients have been attributed to its antiviral activity against human Borna disease virus (BDV) infection which is frequently seen in patients with depressive episodes. In this 8 to 12 week open study of oral amantadine in 30 depressed patients with various states of BDV infection we found a significant antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute infection was cleared in both responders and non-responders, but only in responders peripheral infection was significantly reduced.