[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.

Incidence, characteristics and course of narrow phenotype paediatric bipolar I disorder in the British Isles.

OBJECTIVE: To estimate the surveillance incidence of first-time diagnosis of narrow phenotype bipolar I disorder (NPBDI) in young people under 16 years by consultants in child and adolescent psychiatry (CCAP) in the British Isles and describe symptoms, comorbidity, associated factors, management strategies and clinical outcomes at 1-year follow-up. METHOD: Active prospective surveillance epidemiology was utilised to ask 730 CCAP to report cases of NPBDI using the child and adolescent psychiatry surveillance system. RESULTS: Of the 151 cases of NPBDI reported, 33 (age range 10-15.11 years) met the DSM-IV analytical case definition with 60% having had previously undiagnosed mood episodes. The minimum 12-month incidence of NPBDI in the British Isles was 0.59/100 000 (95% CI 0.41-0.84). Irritability was reported in 72% cases and comorbid conditions in 51.5% cases with 48.5% cases requiring admission to hospital. Relapses occurred in 56.67% cases during the 1-year follow-up. CONCLUSIONS: These rates suggest that the first-time diagnosis of NPBDI in young people <16 years of age by CCAP in the British Isles is infrequent; however, the rates of relapse and admission to hospital warrant close monitoring.

Polypharmacy and bipolar disorder: what's personality got to do with it?

The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n = 89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 ± 1.9 vs. 2.8 ± 1.8, p < 0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 ± 8.9 vs. 25.4 ± 7.6, p < 0.05) and lower conscientiousness (21.9 ± 8.2 vs. 27.9 ± 8.2, p < 0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research.

Increased parental history of bipolar disorder in the United States: association with early age of onset.

OBJECTIVE: Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder. METHOD: Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ2 and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected. RESULTS: After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder. CONCLUSION: Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Katayama et Al.: therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study. Pharmacopsychiatry 2014; 47: 111-114.

Katayama and colleagues proposed in their article a therapeutic window for lamotrigine in affective disorders between 5 and 11 µg/mL. Despite potential differences in lamotrigine metabolism, the results of their retrospective study in a Japanese population match nicely with what we have previously reported in a Caucasian population with rapid cycling bipolar disorder. It is suggested that not only in epilepsy, but also in mood-disordered patients clinicians should rather consider lamotrigine plasma levels than dosage when in doubt about the efficacy of treatment.

Dual disorder: does expert clinical experience support the rationale for cariprazine use?

Comorbid substance use disorder (SUD) in patients with schizophrenia (dual disorder, DD) is a frequent occurrence in the psychiatric clinical practice and is positively associated with poorer outcomes. Despite a very high co-prevalence, clinical guidelines for SUD and severe mental illnesses tend to give limited consideration to co-existing disorders regarding diagnosis and management. This article is the result of a meeting held in February 2023 to discuss common challenges and best clinical practice initiatives for patients with schizophrenia and DD in different treatment settings. The authors identified issues in the clinical approach to DD in schizophrenia spectrum disorders and suggested the most suitable management based on their experience as a group of experts, identifying possible improvement areas. In conclusion, the panel recommends that individuals with DD should be cared for in a single center. Pharmacologic treatment in individuals with DD needing both control of symptoms related to schizophrenia spectrum disorders and substance withdrawal should ideally be based on using a non-sedative antipsychotic with anti-craving activity.

Physical health of patients with bipolar disorder.

OBJECTIVE: This article reviews the characteristics of bipolar disorder and approaches to minimise physical health risks, as well as treatment options, and their influence on patient quality of life (QoL). METHOD: The content of this article is based on the proceedings of a 1-day standalone symposium in November 2011 exploring how to establish a bipolar clinic within the context of existing services in the UK's National Health Service. RESULTS: Bipolar disorder is a common mental disorder and often under-recognised in patients with major depressive episodes. Patients are largely dependent on family and carers to lead normal lifestyles and have difficulties maintaining relationships. Mental health and physical health are closely linked, with risk factors such as weight gain, metabolic syndrome, smoking and diabetes contributing to cardiovascular disease and early death. Antipsychotics may induce treatment-related comorbidities, thus further contributing to a low QoL of patients. Symptoms of comorbidity or depression are frequently relieved through self-medication and substance abuse, thus increasing patient health and suicide risk. Therefore, regular health monitoring and patient education in risk factor minimisation are required. CONCLUSION: Early pharmacotherapeutic and psychoeducational interventions are required to improve treatment outcomes, as well as improving patient understanding of ways to minimise comorbidity development.

Ziprasidone--not haloperidol--induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus.

INTRODUCTION: Here, we present a stem-cell based study on the de-novo generation of beta-III-tubulin-positive neurons after treatment with the classic antipsychotic drug haloperidol or after treatment with the second-generation antipsychotic (SGA) ziprasidone. METHODS: Adult neural stem cells (ANSC) dissociated from the adult mouse hippocampus were expanded in cell culture with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). ANSC differentiated upon withdrawal of EGF and bFGF. RESULTS AND DISCUSSION: Ziprasidone generated significantly more beta-III-tubulin-positive neurons than haloperidol during the differentiation of adult neural stem cells isolated from murine hippocampus (ANSC). We assume that this net increase in neurogenesis by ziprasidone relies on this drug's 5-HT1A receptor affinity, which is not present in the haloperidol molecule, since the inactivation by WAY100621 impeded this process. These data could possibly suggest a clinical relevance for studying antipsychotic drugs in the stem cell paradigm employed in this study.

[Neuroimaging of bipolar disorders]. / Bildgebende Verfahren bei bipolaren Erkrankungen.

During recent years, marked progress has been made both in structural and functional neuroimaging of affective disorders. Structural changes in the limbic system, prefrontal cortex and subcortical regions including their fascicular connections appear to correlate with affective disorders in most, but not all studies. Especially for bipolar disorder, there still is a considerable heterogeneity among the results. Functional neuroimaging (fMRI, SPECT, PET) underlines the importance of paralimbic, cortical and subcortical structures in mood regulation; however, the methodology of these studies is still in its infancy meaning that the results of these studies are not always reproducible. However, in summary it can be expected that with improving methodology functional neuroimaging will play an increasing role in affective, including bipolar, disorders in the near future.

[Differential diagnosis of and pharmacotherapy for bipolar disorder]. / Differenzialdiagnostik und Psychopharmakotherapie bipolarer Störungen.

Bipolar disorders constitute a group of frequent, chronic psychiatric illnesses with a most severe impact on the patient's life. The course can be very individual and heterogeneous, the best known and most frequent manifestations include the classical bipolar I and bipolar II disorders. However, in Germany even typical bipolar I disorders are underdiagnosed and, consequently, undertreated. This is true despite the fact that the number of pharmacological treatment options has rapidly increased during recent years, both in the field of anticonvulsants and atypical antipsychotics. This supplies us today with new therapeutic strategies, not only for acute mania, but also for bipolar depression and maintenance treatment, and it is feasible to assume that there will be more options available within the next few years.

[De-escalation and atypical antipsychotics in the treatment of acute mania]. / Deeskalationstechniken und atypische Neuroleptika in der Behandlung der akuten Manie.

Agitation is a severe clinical state which represents a therapeutic challenge and often forms part of manic or mixed episodes. Therapeutic options for acute mania have been limited for many years to lithium and typical antipsychotics. Besides anticonvulsants, atypical antipsychotics have been increasingly introduced in the last decade after proving their efficacy in this indication. To avoid intramuscular administration and excessive sedation, a therapeutic contact to the often agitated patient is required. De-escalation techniques can be helpful in this respect but also reduce aggressive behaviour on the ward, improve compliance, reduce relapse rates and lead to a better outcome in the long-term course of the illness. Therefore, a basic knowledge about de-escalation techniques in acute manic patients is an important clinical tool which will be critically reviewed. Furthermore, the efficacy and tolerability of atypical antipsychotics in acute mania, such as olanzapine, zotepine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone and asenapine are discussed.

[Cognitive-psychoeducational group programme for bipolar disorder: pilot study with two-year follow-up]. / Kognitiv-psychoedukative Gruppenintervention bei bipolar erkrankten Patienten: Pilotstudie mit Zwei-Jahres-Katamnese.

52 patients with bipolar disorder were treated with psychopharmacotherapy and a cognitive psychoeducational group programme that was established at the Department of Psychiatry and Psychotherapy of the Ludwig Maximilian University, Munich, Germany. The programme covers psychoeducation, identifying and coping with depressive and manic symptoms, relapse prevention and establishing a stable life style. 96 % rated the group to be helpful and felt well informed about their illness. There were significant gains in knowledge (F = 25,714, p < 0.001) and improvements in the severity of the illness (CGI; F = 68,255, p < 0.001) post-treatment. With regard to sociodemographic and clinical variables, only the level of work qualification showed a differential treatment response: patients with higher qualifications had a more favourable course of the illness (F = 4,125, p = 0.048). At one and two year follow-up 25 % and, respectively, 30 % of the sample had to be readmitted. A higher number of previous hospitalisations (p = 0.010) and male sex (p = 0.031) turned out to be significant predictors of relapse (R² = 0.358, p = 0.004) at two year follow-up. This disorder-specific group programme represents a key component of treatment offering emotional support for patients and their relatives. Patients are to be involved in the treatment process and need information about the illness, its psychosocial and pharmacological treatment as well as help in learning practical skills to improve their living with the disease. Being integrated and committed to a supporting network may increase their quality of life.

[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.

The clinical side of bipolar disorders.

This article summarizes key facts on the epidemiology, diagnosis and clinical treatment of bipolar disorder. Bipolar disorder is a common mental disorder with a high disease burden, but still does not get the attention it deserves in research and clinical training. The nature of the disorder is complex, but it is apparent that biological factors are decisive. Thus, understanding the biological systems and cycles affected will become crucial for developing more targeted interventions. Currently, standard treatments seem to have a low specificity for Bipolar Disorder, and only few experimental interventions target directly potential underlying disturbances as HPA axis or circadian clock dysregulation. Systemic analysing and modelling of bipolar disorder is a novel approach which might open up new ways in developing more selective therapies.

[Acute and long-term treatment for bipolar depression]. / Akut- und Langzeittherapie der bipolaren Depressionen.

Bipolar depression is linked with substantial burden and a high suicide risk, making a rapid and highly efficacious treatment mandatory. However, similar to mania, aspects of long-term treatment should already be considered at treatment initiation. With comparable efficacy, drugs with a beneficial safety and tolerability profile should be preferred. Additional psychotherapy can also noticeably improve both short- and long-term outcome of bipolar depression. Electroconvulsive therapy (ECT) still has its place in severe, treatment-resistant bipolar depression. Whereas ECT is a domain of specialised centres, correct diagnosis and both pharmacological and psychotherapeutic treatment initiation are essential tasks of primary care practitioners and secondary care psychiatrists.

Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal.

Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.

Preliminary results of a fine-grain analysis of mood swings and treatment modalities of bipolar I and II patients using the daily prospective life-chart-methodology.

OBJECTIVE: The study aimed to increase the knowledge about the detailed course differences between different forms of bipolar disorder. METHOD: Using the prospective life-chart-clinician version, we compared the fine-grain analysis of mood swings and treatment modalities of 18 bipolar II with 31 bipolar I patients. RESULTS: During an observational period of a mean of 26 months we observed an increase of euthymic days, and a decrease of (sub)depressive and (hypo)manic days. Days in a (sub)depressed state were more frequent than days of (hypo)mania as well as days of subdepression or hypomania in comparison to days of full-blown depression or mania. Bipolar II patients showed an increase in hypomanic days receiving more frequently antidepressants. Bipolar I patients, with a decrease of manic days, were significantly taking more often mood stabilizers. CONCLUSION: Treatment in a specialized bipolar clinic improves the overall outcome, but bipolar II disorder seems to be still treated sub-optimally with a possible iatrogenic increase of hypomanic days.

[Specific aspects of treatment for women with bipolar affliction]. / Spezifische Behandlungsaspekte bipolar erkrankter Frauen.

This manuscript summarizes specific issues in the disease course and pharmacological treatment of women with bipolar disorders. Gender differences relevant to the female biology manifest in symptoms, outcome, and course. The preponderance of depressive symptoms is typical, and the risk of rapid cycling is estimated to be eight times higher for women than for men. Comorbid anxiety and eating disorders occur more frequently in female patients. In planning treatment it is important to take fertility, contraception, and pregnancy into consideration and adjust the pharmacotherapy to harmonize with the patient's current phase of life. Little is known about potential sexual dysfunctions of bipolar women. Further research should include clinical and observational studies focusing on gender-specific differences in symptomatology, treatment, and long-term outcome of bipolar disorders.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.