REVIEWToward stratified treatments for bipolar disorders
Introduction
Psychiatric research goes to great lengths to develop tests that can predict specific therapeutic successes (Frey et al., 2013). Such tests allow for adjustment of therapies to pathological processes and are of clinical relevance if the estimation of therapeutic success based on conventional diagnostic methods is imprecise. More specifically, stratified medicine intends to bring into line diagnosis, therapy, and prevention with the genetic predisposition of patients. In the case of bipolar disorders, no risk genes and no genes associated with treatment success have been reliably identified. In this review, the term “stratified medicine” has been broadened to include all kinds of predictors of therapy success. At the end of the article, we focus on the potential of genetic and epigenetic markers in bipolar disorders.
Section snippets
Why stratifying treatments for bipolar disorders?
There is much evidence that conventional diagnosis of bipolar disorders is imprecise (Angst, 2004, Angst, 2008, Angst et al., 2010, Simpson et al., 2002, Zimmermann et al., 2009). While international treatment guidelines of frequent psychiatric disorders, such as major depression or schizophrenia, are relatively consistent, the guidelines for bipolar disorders are strikingly inconsistent and heterogeneous (Nivoli et al., 2011). This is particularly the case for bipolar depression in which
Stratification based on psychopathological characteristics
The American Psychiatric Association׳s third edition of the Diagnostic and Statistical Manual (DSM-III, 1980) aimed to operationalize clinical psychiatric diagnosis. This was required in order to study scientific diagnosis and markers regarding prediction of treatment success. A group of experts defined clusters of symptom patterns for courses as diagnostic criteria based on their clinical experience. In this way, defined diagnoses have been validated by epidemiological methods. Validation was
The concept of endophenotypes
Gottesman and Shields (1973) recognized early a fundamental problem of psychiatric genetics. Psychiatric conditions, as defined in the DSM and other established diagnostic manuals, do not represent adequate phenotypes for research since they are conceptualized as syndromes and are not related to mechanisms of illness. Furthermore, they assumed a long pathway from genes to clinical symptoms, which is difficult to reveal because of complex gene-by-gene interactions and gene-by-environment
Stratified psychotherapy of bipolar disorders
Apart from psychoeducation, many forms of psychotherapy in bipolar disorders have proven effective. Interpersonal and social rhythm therapy, cognitive behavioral therapy, and family-focused therapy increase the probability of recovery, decrease time to recovery, and improve interpersonal skills and life satisfaction (Miklowitz, 2006). Similarly, pharmacotherapy response rates are typically low to moderate and scientific criteria on the selection of specific types of psychotherapy related to
Adverse drug reactions
Frequent problems with compliance and common somatic comorbidities in bipolar disorders means that drugs are not only chosen based on their effect but also based on their profile of adverse drug reactions (ADR). Stratification based on ADR profiles is relatively well advanced. The corrected QT interval derived from modern electrocardiogram machines is increasingly used to assess the threat of severe cardiac ADRs. This is particularly of great importance when drugs are combined since a
Genetics
Genetic factors constitute approximately 90% of bipolar I disorder causes (Kieseppa et al., 2004, McGuffin et al., 2003). However, identification of individual risk genes is still unsuccessful. This is striking since risk genes have been found for complex genetic diseases with lower heritability than bipolar disorder, such as diabetes mellitus, Alzheimer׳s disease, and breast cancer (Hasler et al., 2006).
As mentioned above, a major problem of psychiatric genetics is the fact that psychiatric
Epigenetics
Each cell of our body contains an epigenetic imprint of experience in its genome. Some epigenetic changes can be inherited through multiple generations. The epigenetic patterning occurs at the level of whole chromosomes and of large chromosomal regions down to the single nucleotide level. A relatively well-examined epigenetic change involves the acetylation of histones leading to the local loosening of DNA and increased gene reading in this section. In contrast, histone methylation inhibits
Conclusion
The current process of diagnosing bipolar disorders based solely on clinical symptoms has crucial weaknesses. Evidence for these weaknesses are low average response rates, long phases of treatment adjustment, and inconsistent treatment guidelines.
Employing methods of neuropsychology, neuroradiology, immunology, genetics, and epigenetics, biomarkers have been proposed and evaluated. Table 2 summarizes the most promising clinical and biological markers to predict responses to specific treatments.
Author disclosure
Both, G.H. and A.W. were involved in the literature search and in writing the paper. The University of Bern alone supported the writing of this paper.
G.H. has received speaker and consulting honoraria from Lundbeck, AstraZeneca, Servier, Eli Lilly and Novartis. These honoraria are not related to the writing of this article. A.W. did not receive any honoraria from industry.
Role of funding source
None.
Contributors
G.H. and A.W. No one else.
Conflict of interest
None.
Acknowledgment
None.
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2020, European NeuropsychopharmacologyCitation Excerpt :Heritability estimates for BD have typically been reported to be between 60%−80% (Lescai et al., 2017; Smoller, Jordan W.; Finn, 2003), with evidence for genetic heterogeneity between endophenotypes (Charney et al., 2017). In an era where current research in psychiatry attempts to advance from blockbuster psychiatry to ¨stratified¨ psychiatry, bringing into line diagnosis, treatment, and possibly even prevention, with each patient's genetic predisposition (Hasler and Wolf, 2015; Murawiec and Popovic, 2015), response to lithium may help to identify patients with different phenotypes. Lithium is the gold standard for the treatment for BD, over 60 years after its introduction into clinical practice (Alda, 2015; Malhi and Outhred, 2016).
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2020, Journal of Affective DisordersCitation Excerpt :All these may result in PBD patients’ being poorer in overall daily functioning. For the reason that the pathophysiological mechanism of bipolar disorder remains to be further studied, the cognition over the differences between different mood states is still limited (Hasler and Wolf, 2015). Bipolar disorder may develop during the process of brain development and it often has close correlation with impaired memory and cognitive deficits, which are not only present during mood episodes but also during mood remission of the disease (Bora et al., 2009; Martinez-Aran et al., 2004; Robinson and Ferrier, 2006).
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2020, Neurobiology of Bipolar Disorder: Road to Novel TherapeuticsStructural characteristics of the brain reward circuit regions in patients with bipolar I disorder: A voxel-based morphometric study
2017, Psychiatry Research - NeuroimagingCitation Excerpt :This disorder (BD) has been associated with a high societal burden (Dilsaver, 2011). From a clinical perspective, BD is defined as a heterogeneous group of disorders (Hägele et al., 2015; Hasler and Wolf, 2015). Therefore, it is difficult to identify the pathophysiological mechanisms underpinning BD-I. Thus, the psychopharmacological treatments that are presently available are only partially effective (Cuthbert and Insel, 2013).
The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies
2017, Neuroscience and Biobehavioral ReviewsProteomics strategies for bipolar disorder evaluation: From sample preparation to validation
2016, Journal of ProteomicsCitation Excerpt :The tissue must be checked to find out physiological alterations caused by trauma, tumors or stroke, for example. Two aspects have been considered in recent works: (I) a comparison between BD samples and, at least, other mood disease (for example, schizophrenia), in proteomic studies, and (II) the necessity of novel clinical biomarkers and clinical markers for increasing the efficacy of available treatments and for improving the chances of developing novel therapeutic approaches [12]. Currently, BD studies following proteomics approaches entail the comparison of BD disease versus other mood diseases with the aim to find biomarkers of diagnosis and prognosis.