[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.

Influence of DGKH variants on amygdala volume in patients with bipolar affective disorder and schizophrenia.

The diacylglycerol kinase eta (DGKH) gene, first identified in a genome-wide association study, is one of the few replicated risk genes of bipolar affective disorder (BD). Following initial positive studies, it not only was found to be associated with BD but also implicated in the etiology of other psychiatric disorders featuring affective symptoms, rendering DGKH a cross-disorder risk gene. However, the (patho-)physiological role of the encoded enzyme is still elusive. In the present study, we investigated primarily the influence of a risk haplotype on amygdala volume in patients suffering from schizophrenia or BD as well as healthy controls and four single nucleotide polymorphisms conveying risk. There was a significant association of the DGKH risk haplotype with increased amygdala volume in BD, but not in schizophrenia or healthy controls. These findings add to the notion of a role of DGKH in the pathogenesis of BD.

The DTNBP1 (dysbindin-1) gene variant rs2619522 is associated with variation of hippocampal and prefrontal grey matter volumes in humans.

DTNBP1 is one of the most established susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in this severe disorder. Consistent with these findings, the encoded protein dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to investigate the effects of two single nucleotide polymorphisms of DTNBP1 on grey matter volumes in human subjects using voxel-based morphometry. Seventy-two subjects were included and genotyped with respect to two single nucleotide polymorphisms of DTNBP1 (rs2619522 and rs1018381). All participants underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analysed using standard procedures as implemented in SPM5 (Statistical Parametric Mapping), in particular the voxel-based morphometry (VBM) toolbox. We found significant effects of the DTNBP1 SNP rs2619522 bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. Carriers of the G allele showed significantly higher grey matter volumes in these brain regions than T/T homozygotes. Compatible with previous findings on a role of dysbindin in hippocampal functions as well as in major psychoses, the present study provides first direct in vivo evidence that the DTNBP1 SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the hippocampus.

DISC1 (disrupted-in-schizophrenia 1) is associated with cortical grey matter volumes in the human brain: a voxel-based morphometry (VBM) study.

DISC1 (Disrupted-In-Schizophrenia 1), one of the top candidate genes for schizophrenia, has been associated with a range of major mental illnesses over the last two decades. DISC1 is crucially involved in neurodevelopmental processes of the human brain. Several haplotypes and single nucleotide polymorphisms of DISC1 have been associated with changes of grey matter volumes in brain regions known to be altered in schizophrenia and other psychiatric disorders. The aim of the present study was to investigate the effects of two single nucleotide polymorphisms (SNPs) of DISC1 on grey matter volumes in human subjects using voxel-based morphometry (VBM). 114/113 participating subjects (psychiatric patients and healthy controls) were genotyped with respect to two at-risk SNPs of DISC1, rs6675281 and rs821616. All participants underwent structural magnetic resonance imaging (MRI). MRI data was statistically analyzed using voxel-based morphometry. We found significant alterations of grey matter volumes in prefrontal and temporal brain regions in association with rs6675281 and rs821616. These effects of DISC1 polymorphisms on brain morphology provide further support for an involvement of DISC1 in the neurobiology of major psychiatric disorders such as schizophrenia.

[S3 guidelines on diagnostics and therapy of bipolar disorders: development process and essential recommendations]. / S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen: Entwicklungsprozess und wesentliche Empfehlungen.

Bipolar disorders are severe psychiatric disorders with extensive individual and health economic consequences. Starting in 2007 the first German evidence and consensus based guideline for diagnostics and treatment of bipolar disorders was developed which holds the potential of increasing confidence of therapists, patients and relatives in the decision-making process and improving healthcare service experiences of patients and relatives. Apart from recommendations for diagnostics and treatment the guidelines provide those for trialogue action, knowledge transfer and self-help and for strategies for healthcare provision of this complex disorder. In the present article the methodology and essential recommendations are outlined and complemented in specific topics by corresponding articles in this special issue. Due to restrictions of the length of this presentation there is the need to refer to the comprehensive version of the guidelines at several points also regarding a detailed discussion of the limitations.

Thalamic volumes in patients with bipolar disorder.

There are several hypotheses on functional neuronal networks that modulate mood states and which might form the neuroanatomical basis of bipolar disorder. The thalamus has been reported to be a key structure within the circuits that modulate mood states and might thus play an important role within the aetiology of the bipolar affective disorder. Nevertheless, structural brain imaging studies on the thalamus volume of bipolar patients have shown heterogeneous results. Using structural MRI scanning, we compared the thalamus volume of 41 euthymic bipolar patients to the thalamus volume of 41 well-matched healthy controls. Taking the concomitant medication as a co-variable within the patient group, the analysis of variance revealed a significantly smaller relative volume of the right thalamus in patients not treated with lithium when compared with healthy controls. In contrast, there are no significant differences concerning the thalamus volume between all euthymic bipolar patients and healthy controls. The study only shows findings of a transverse section. No longitudinal analysis was performed. More detailed information on patients' pharmacological histories could not be obtained. In conclusion, this result may be interpreted as an indication of the impact of the thalamus in the pathogenesis of the bipolar I disorder and emphasises the need for further longitudinal studies in bipolar patients with special attention paid to the concomitant medication, in particular to the role of lithium.

Increased right amygdala volume in lithium-treated patients with bipolar I disorder.

OBJECTIVE: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. METHOD: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. RESULTS: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. CONCLUSION: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Neurocognitive functions in euthymic bipolar patients.

OBJECTIVE: Meta-analytic findings support the hypothesis of specific neurocognitive deficits for bipolar patients in the domains of attention, processing speed, memory and executive functions. This study aims to show neurocognitive impairment in euthymic patients with bipolar I disorder compared with healthy controls while detailing the impact of medication side-effects or illness characteristics on neuropsychological test performance. METHOD: Forty euthymic patients with bipolar I disorder were compared with 40 healthy controls in a cross-sectional design. Clinical features and neuropsychological measures of IQ, psychomotor speed, verbal fluency, learning and memory, executive functions and attention were assessed. RESULTS: Patients without antipsychotic drug use did not differ significantly from healthy controls in any neuropsychological measure. Yet patients treated with antipsychotics showed significant underperformance in the domains of semantic fluency, verbal learning and recognition memory as well as executive functions related to planning abilities, even when clinical features were controlled for. CONCLUSION: The impact of antipsychotic medication needs to be further clarified for euthymic bipolar patients and should be considered when neuropsychological test performance is interpreted.

Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.

OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

[Drug addiction in young prison inmates with and without attention deficit hyperactivity disorder (ADHD)]. / Suchtmittelgebrauch bei jungen erwachsenen Straftätern mit und ohne Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS).

Prospective studies of children with ADHD have shown a high level of substance use disorder comorbidity, particularly when associated with social maladaptation and antisocial behavior. Conversely, studies of drug abusing participants and delinquents revealed a high prevalence of ADHD comorbidity. In this study 129 young male prison inmates were systematically examined for ADHD and substance use disorders. 64,3 % showed harmful alcohol consumption. 67,4 % fulfilled DSM-IV criteria for any drug abuse or dependence. 28,8 % of these participants were diagnosed with ADHD, combined type, other 52,1 % showed ADHD residual type. Opioid dependence was more common in delinquents without ADHD. Addicted delinquents with ADHD showed worse social environment and a higher degree of psychopathology, including externalizing and internalizing behavior, compared to addicted delinquents without ADHD. Neuroticism and conscientiousness ratings of the addicted ADHD group, but not of those without ADHD, differed from non-addicted delinquents. The results underline the need of adequate therapeutic programs for addicted young prison inmates considering ADHD comorbidity, which is associated with additional psychopathology and social problems.

[Magnetic resonance spectroscopy in schizophrenia. Possibilities and limitations]. / Magnetresonanzspektroskopie bei Schizophrenie. Möglichkeiten und Grenzen.

Magnetic resonance spectroscopy is a noninvasive investigative technique for in vivo detection of biochemical changes in neuropsychiatric disorders for which especially proton (1H-MRS) and phosphorus (31P-MRS) magnetic resonance spectroscopy have been used. In this review we explain the principles of MRS and summarize the studies in schizophrenia. A systematic literature review was carried out for 1H-MRS studies investigating schizophrenic patients compared to controls. The inconsistent results in the cited studies may be due to different study population, specific neuroimaging technique, and selected brain regions. Frequent findings are decreased PME and increased PDE concentrations (31P-MRS) linked to altered metabolism of membrane phospholipids and decreased N-acetylaspartate (NAA) or NAA/choline ratio (1H-MRS) linked to neuronal damage in frontal (DLPFC) or temporal regions in patients with schizophrenia. These results contribute to the disturbed frontotemporal-thalamic network assumed in schizophrenia and are supported by additional functional neuroimaging, MRI morphometry, and neuropsychological evaluation. The combination of the described investigative techniques with MRS in follow-up studies may provide more specific clues for understanding the pathogenesis and disease course in schizophrenia.

[Changes in brain structure caused by neuroleptic medication]. / Veränderungen der Hirnstruktur durch neuroleptische Medikation.

A couple of studies showed that neuroleptic treatment affects brain morphology. This paper reviews findings of volumetric longitudinal studies on treated schizophrenics, longitudinal studies considering the effect of different neuroleptic treatments on brain morphology, and studies on neuroleptic-naive patients with schizophrenia. The latter studies show enlargement of ventricles, diminished volume of the thalamus and reduced gray matter in different cortical regions. Findings on the nucleus caudatus, hippocampus, and amygdala are inconsistent. The volumes of the putamen and globus pallidus are unchanged. Medication with typical antipsychotics leads to increased volume of the nucleus caudatus while atypical antipsychotics do not change the volume of the nucleus caudatus.

[Changes in brain structure in bipolar affective disorders]. / Hirnstrukturelle Veränderungen bei bipolaren affektiven Störungen.

The neurobiological basis of bipolar affective disorders is unknown. However, neuroanatomic circuits of mood regulation have been hypothesized. Neuroimaging revealed volumetric changes of specific brain structures in these circuits. The most prominent abnormality is enlargement of the amygdala. In addition there might be structural changes in the frontal lobe, cerebellum, and pituitary. The findings in bipolar disorder differ from those in unipolar depression and schizophrenia. For further identification of the neurobiological basis of bipolar disorders, structural neuroimaging combined with functional neuroimaging such as magnetic resonance spectroscopy, neuroendocrinological studies, and genetical analyses are required to subgroup patients with bipolar disorder by diagnostic, prognostic, and therapeutic criteria.

[The importance of interneurons in schizophrenic and affective disorders]. / Die Bedeutung von Interneuronen bei affektiven und schizophrenen Erkrankungen.

In brains of patients with schizophrenic and affective disorders pathomorphological changes have been shown focussing in frontal and temporal cortex. The volume reduction in prefrontal cortex of schizophrenic patients is hypothesized to be based on a reduction of neuropil. A decrease of synaptic proteins and a decrease of dendritic spines of pyramidal cells can additionally be the origin of disconnections of neurons. Affection of the glutamatergic, GABA-ergic and dopaminergic system and reduction of interneurons could be the correlate of a deficient neuronal network which might be combined with exogen factors generate psychotic symptoms. Reelin and associated proteins are candidate molecules. Their dysregulation might explain essential features of the dysfunctional network of schizophrenia.

Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder.

Various polymorphisms of the X-chromosomal monoamine oxidase A (MAO-A) gene were investigated for association with affective disorders. However, none of the studied variants could consistently be associated with either major depressive or bipolar affective disorder. Recently, a positive association between panic disorder and a novel functional repeat polymorphism in the MAO-A gene promoter, with the longer alleles being more active, was reported. Since monoaminergic neurotransmission is supposed to play an important role in affective disorders, we investigated a potential association of this polymorphism with major depressive illness in a sample of 146 unrelated patients of German descent and a control group of 101 individuals with a negative life history for affective disorders. Similarly to the recent findings in panic disorder, we observed a significantly increased frequency of genotypes containing only long alleles in female patients with recurrent major depression in comparison with age- and sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801-803, 2000.