REVIEW
Toward stratified treatments for bipolar disorders

https://doi.org/10.1016/j.euroneuro.2014.12.006Get rights and content

Abstract

In bipolar disorders, there are unclear diagnostic boundaries with unipolar depression and schizophrenia, inconsistency of treatment guidelines, relatively long trial-and-error phases of treatment optimization, and increasing use of complex combination therapies lacking empirical evidence. These suggest that the current definition of bipolar disorders based on clinical symptoms reflects a clinically and etiologically heterogeneous entity. Stratification of treatments for bipolar disorders based on biomarkers and improved clinical markers are greatly needed to increase the efficacy of currently available treatments and improve the chances of developing novel therapeutic approaches. This review provides a theoretical framework to identify biomarkers and summarizes the most promising markers for stratification regarding beneficial and adverse treatment effects. State and stage specifiers, neuropsychological tests, neuroimaging, and genetic and epigenetic biomarkers will be discussed with respect to their ability to predict the response to specific pharmacological and psychosocial psychotherapies for bipolar disorders. To date, the most reliable markers are derived from psychopathology and history-taking, while no biomarker has been found that reliably predicts individual treatment responses. This review underlines both the importance of clinical diagnostic skills and the need for biological research to identify markers that will allow the targeting of treatment specifically to sub-populations of bipolar patients who are more likely to benefit from a specific treatment and less likely to develop adverse reactions.

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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