DSM-5 Criteria for Bipolar Disorder May Further Cloud Diagnosis

Fran Lowry

May 14, 2013

The soon-to-be released fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) will likely further confuse the diagnosis and treatment of bipolar disorder (BD), according to one expert.

A comment written by Gin Malhi, MD, of the University of Sydney in Australia and published online May 10 in the Lancet as part of a special series on BD expresses concern that the inclusion in the DSM-5 of a "mixed states specifier," which is broadly defined as the coexistence of depressive and manic features, may lead to diagnostic confusion and complicate treatment.

Dr. Malhi notes that mixed states have long contributed to the concept of manic-depressive illness and that the criteria for mixed states have narrowed in successive editions of the DSM, from DSM-I to DSM-IV, from manic-depressive reaction mixed type to mixed episodes.

However, in the DSM-5, this trend is reversed, and the mixed episode diagnosis has been replaced in the DSM-5 by a mixed features specifier (MxFS).

The MxFS, Dr. Malhi explains, "denotes the concurrence of at least three symptoms from the opposite pole of the illness within either a manic or hypomanic, or depressive, episode."

He adds that this definition is more flexible than the DSM-IV criteria for a BD mixed episode, in which the complete criteria for both a depressive and a manic episode had to be met for 1 week.

"In practice, such a high threshold for diagnosis was often unattainable and consequently mixed episodes had low clinical use. Furthermore, the absence of any subtypes — for example indicating the predominance of depressive or manic symptoms — stifled research," Dr. Malhi notes.

Although a change in the diagnostic criteria was necessary, Dr. Malhi notes that it is unclear whether the MxFS will fix the problem and improve diagnosis.

He expresses concern that the MxFS will increase the diagnosis of bipolarity and may identify missed diagnoses but that because of its low specificity, it will simultaneously increase the likelihood of misdiagnosis.

"The risk is that [the diagnostic criterion of mixed states] will be used loosely and its application will expand far beyond bipolar disorder type I and across the whole bipolar spectrum, without any prognostic significance of therapeutic benefit," he writes.

Genetic Basis for BD

In the first Lancet series article, researchers note that compelling evidence suggests that BD has genetic underpinnings, and they review current knowledge in this area.

Nick Craddock, MD, from the School of Medicine, Cardiff University, in the United Kingdom, and Pamela Sklar, MD, from the Icahn School of Medicine at Mount Sinai, in New York City, note that studies of families and twins highlight the importance of genetic factors affecting susceptibility to BP and suggest "substantial genetic and phenotypic complexity."

Significant associations with BP and several common polymorphisms, including variants with the genes CACNA1C, ODZ4, and NCAN, have been discovered, they note.

They add that a "notable finding" is the overlap of susceptibility between BP and schizophrenia for several of these polymorphisms.

Further investigation of these genetic findings "might eventually pave the way for major improvements in clinical management" of BP, they write.

"The association between genotype and phenotype for psychiatric disorders is clearly complex. Reductionist thinking has no place, and to think of any case as being either genetic or environmental, or to talk about a gene for bipolar disorder, makes no sense. The key point is that most cases of bipolar disorder involve the interplay of several genes or more complex genetic mechanisms, together with the effects of the environment, and chance," Dr. Craddock said in a statement.

BD researchers now need to follow up genetic studies with imaging and psychological studies to try to unravel the complex biological mechanisms involved in BP and bring biological understanding closer to the experience of the patient.

"While several genes which increase a patient's risk of acquiring bipolar disorder have been discovered to date, no clear biological mechanism to explain why these genes affect a person's risk of developing bipolar has been elucidated," the authors note.

Neuroimaging for BD Diagnosis

In the second series article, David J. Kupfer, MD, DSM-5 Task Force Chair, and Mary L. Phillips, MD, both from the University of Pittsburgh, in Pennsylvania, write that neuroimaging studies could eventually discover biomarkers that could help determine where a patient might lie on the behavioral scale of BD and also help identify biological targets for treatment, not only for BD but for all affective disorders.

The article notes the substantial difficulties in diagnosing BD, including misdiagnosis of BD as unipolar depression, a substantial delay of 5 to 10 years between the onset of BD and diagnosis, and the fact that depressive symptoms are more prevalent than manic symptoms, and so people are more likely to seek treatment for depression.

This can be a major problem because medication used to treat unipolar depression is not the same as that used to treat BD and could even exacerbate the manic symptoms seen in BD, the authors write.

"Identifying objective biomarkers that differ between bipolar and unipolar depression would not only lead to more accurate diagnosis but potentially to new, personalized treatments, yet very little research has been undertaken in this area. For instance, very few neuroimaging studies have been done in which the brains of people with bipolar disorder have been compared to those of people with unipolar disorder, and further research into this area is urgently needed," Dr. Phillips said in a statement.

Obstacles to New Treatments

In the third series article, authors John R. Geddes, MD, from the University of Oxford, in the United Kingdom, and David J. Miklowitz, PhD, from the University of California, Los Angeles (UCLA), write that overall, advances in drug treatment remain "quite modest."

There have been no fundamental advances in the search for more effective treatment for BD in the last 20 years, despite a substantial expansion of research into the subject, and development of effective treatments is being hampered by scarce knowledge of basic disease mechanisms or clear targets for medicines, they note.

Although antidepressants are commonly used to treat the depressive phase of the disorder, there is scarce evidence for their efficacy, Dr. Geddes and Dr. Miklowitz point out.

Lithium, first introduced in 1949, remains the best-established long-term treatment for BD, but its benefits are restricted by adverse effects, and alternatives are often needed for long-term treatment, they note.

"Combining psychosocial treatments, which can include not just psychotherapy for the patient, but family therapy involving education for their family or caregiver, with mood stabilising drugs, might well be one of the most promising lines of treatment for bipolar disorder," Dr. Geddes writes.

"However, drug and psychological treatment studies have largely proceeded independently of one another, and research including both would help to move the field forward."

Dr. Malhi, Dr. Craddock, Dr. Sklar, Dr. Phillips, and Dr. Kupfer report no relevant financial relationships. Dr. Geddes reports financial relationships with the UK Medical Research Council, the European Union, the National Institute of Health Research, and the Stanley Medical Research Institute. He also reports that he was expert witness for Dr. Reddys Laboratories (India) and is chief investigator on the CEQUEL trial, to which GlaxoSmithKline has contributed and supplied investigational drugs and placebo. Dr. Miklowitz reports financial relationships with the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, the Danny Alberts Foundation, the Daniel and Diana Attias Family Foundation, the Carl and Roberta Deutsch Foundation, and the Kayne Foundation.

Lancet. Published online May 10, 2013. Series Article 1, Series Article 2, Series Article 3, Comment

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