Elsevier

Biological Psychiatry

Volume 73, Issue 2, 15 January 2013, Pages 111-118
Biological Psychiatry

Review
Distinguishing between Unipolar Depression and Bipolar Depression: Current and Future Clinical and Neuroimaging Perspectives

https://doi.org/10.1016/j.biopsych.2012.06.010Get rights and content

Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date have directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward, and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a call to action to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at-risk individuals, and more novel neuroimaging approaches, such as connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD and biological targets for more personalized treatment and new treatment developments for BD and UD depression.

Section snippets

The Difficulty in Differentiating between BD and UD Depression

Only 20% of BD individuals during a depressive episode receive the correct diagnosis of BD within the first year of seeking treatment (4), and latency from onset to diagnosis and appropriate treatment averages 5 to 10 years (5, 6). Close to 60% of BD individuals are initially diagnosed as having UD depression (3, 4). Furthermore, despite notions that BD depression may be associated with more psychosis than UD depression, it remains extremely difficult to distinguish depressed patients with BD

Strategies to Identify BD in Depressed Individuals

Clinical strategies have been developed to help detect subthreshold hypomanic symptoms in depressed individuals. These include self- and clinician-administered rating scales, including Bipolar Inventory Symptoms Scale (22), Mood Disorder Questionnaire (23), Screening Assessment of Depression Polarity (24), Hypomania Checklist (25), Bipolar Spectrum Diagnostic Scale (26), and Probabilistic Approach for Bipolar Depression (27). These rating scales vary somewhat, but most include items believed to

Neuroimaging Studies Directly Comparing Individuals with BD Depression Versus UD Depression

Original research studies directly comparing individuals with BD depression with individuals with UD depression were identified through a comprehensive MEDLINE, EMBASE, and PsycINFO search of the English language literature covering publications between January 2000 and February 2012. The search keywords were bipolar disorder, major depressive disorder, and magnetic resonance imaging. Additional articles were identified through the reference lists of these papers.

Studies were included if they

Structural Neuroimaging Studies Directly Comparing Unipolar and Bipolar Depression

One study (51) used diffusion tensor imaging to examine whole-brain fractional anisotropy (FA) in 15 BD-I depressed, 16 UD depressed, and 24 healthy adults. Decreased FA in the left superior longitudinal fasciculus was found in BD versus UD depressed and healthy individuals. Decreased FA was also found in the right uncinate fasciculus in BD depressed versus healthy individuals. Decreased FA was found in the left inferior longitudinal fasciculus in UD depressed versus healthy individuals. These

Functional Neuroimaging Studies Directly Comparing Unipolar and Bipolar Depression

Two studies (61, 62) employed a well-validated emotional facial labeling paradigm to examine the functional integrity of emotion-processing neural circuitry. The paradigm involved displaying negative (fear and sad) and positive (happy) facial expressions as important signals of external threat (fear), internal distress (sad), and social approval (happy) of both prototypical (intense) and mild intensities of each emotion, together with neutral expressions. Fifteen BD-I depressed, 15 BD-I

Neural Circuitry Abnormalities That Differentiate BD from UD in Depressive Episode: Toward Biomarkers of BD

The very small number of structural neuroimaging studies indicates three main findings. First, BD depressed individuals may display more significant abnormalities than UD depressed individuals in white matter connecting key regions in emotion processing and regulation neural circuitry (51). Axonal disorganization, axonal demyelization, or apoptosis, manifested as white matter tract abnormalities, might be related to altered expression of oligodendrocyte and myelin genes (65). Furthermore, lower

Future Approaches in Neuroimaging Research Comparing BD and UD Depression

Here, we highlight novel approaches that should be the focus of future neuroimaging studies of BD and UD depression. These include dimensional approaches, studies of at-risk individuals, and novel neuroimaging approaches.

Dimensional Approaches

An increasing literature conceptualizes BD and recurrent UD along a spectrum of affective disorders, with increasing bipolarity evident in the progression from UD to BD (16, 18, 21, 80, 81).

For example, recent re-analyses of two epidemiologic studies have demonstrated that the dichotomy unipolar/bipolar is questionable and that hypomanic syndromes that do not meet DSM-IV criteria for BD-II are present in about 40% of individuals with recurrent UD (15, 20). The prospective longitudinal study

Studies of Individuals at Risk of Future Affective Disorders

Studies of individuals genetically, or symptomatically, at risk of future affective disorders, including UD and BD, allow identification of biomarkers that may reflect underlying pathophysiologic processes conferring risk or resilience toward future development of these disorders. Prospective, longitudinal studies of these individuals are needed to determine whether abnormalities in neural circuitries identified by neuroimaging predict future development of affective disorders across the

Novel Neuroimaging Approaches

In addition to the development of magnetic resonance imaging technologies, several analytical advances in neuroimaging are under current development. The field is now shifting from conventional analyses of neural activity to more advanced analyses based on functional integration within specific neural circuitries, including analyses of functional (e.g., psychological-physiological interaction [87]) and effective (e.g., dynamic causal modeling [62, 88]) connectivity and resting state

Summary

While BD and UD depression often remain extremely difficult to distinguish in clinical practice, promising findings from studies using different neuroimaging modalities indicate that neuroimaging measures might identify biomarkers to help differentiate BD from UD depression. In parallel, dimensional approaches, including the RDoC initiative, have the potential to help redefine bipolarity in terms of different underlying pathophysiological dimensions. Such approaches may facilitate

References (96)

  • S.C. Caetano et al.

    MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals

    Psychiatry Res

    (2001)
  • G. Delvecchio et al.

    Common and distinct neural correlates of emotional processing in bipolar disorder and major depressive disorder: A voxel-based meta-analysis of functional magnetic resonance imaging studies

    Eur Neuropsychopharmacol

    (2012)
  • B. Hallahan et al.

    Structural magnetic resonance imaging in bipolar disorder: An international collaborative mega-analysis of individual adult patient data

    Biol Psychiatry

    (2011)
  • J. Houenou et al.

    Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses

    J Affect Disord

    (2011)
  • D. Arnone et al.

    Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses

    Eur Neuropsychopharmacol

    (2012)
  • J. Savitz et al.

    Bipolar and major depressive disorder: Neuroimaging the developmental-degenerative divide

    Neurosci Biobehav Rev

    (2009)
  • A. Versace et al.

    Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression

    Biol Psychiatry

    (2010)
  • J.B. Savitz et al.

    Habenula volume in bipolar disorder and major depressive disorder: A high-resolution magnetic resonance imaging study

    Biol Psychiatry

    (2011)
  • D.A. Pizzagalli et al.

    Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task

    Biol Psychiatry

    (2008)
  • J.R. Almeida et al.

    Elevated amygdala activity to sad facial expressions: A state marker of bipolar but not unipolar depression

    Biol Psychiatry

    (2010)
  • J.R. Almeida et al.

    Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression

    Biol Psychiatry

    (2009)
  • J.V. Taylor Tavares et al.

    Neural basis of abnormal response to negative feedback in unmedicated mood disorders

    Neuroimage

    (2008)
  • K. Mahon et al.

    A role for white matter abnormalities in the pathophysiology of bipolar disorder

    Neurosci Biobehav Rev

    (2010)
  • G. Rajkowska et al.

    Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder

    Biol Psychiatry

    (2001)
  • D. Tkachev et al.

    Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

    Lancet

    (2003)
  • H. Soderlund et al.

    High prevalence of white matter hyperintensities in normal aging: Relation to blood pressure and cognition

    Cortex

    (2003)
  • I.K. Lyoo et al.

    White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders

    Compr Psychiatry

    (2002)
  • M. Biondi et al.

    Dimensional psychopathology of depression: Detection of an ‘activation’ dimension in unipolar depressed outpatients

    J Affect Disord

    (2005)
  • G.B. Cassano et al.

    The structure of lifetime manic–hypomanic spectrum

    J Affect Disord

    (2009)
  • K.J. Friston et al.

    Psychophysiological and modulatory interactions in neuroimaging

    Neuroimage

    (1997)
  • K.J. Friston et al.

    Dynamic causal modelling

    Neuroimage

    (2003)
  • M.M. Plichta et al.

    Test–retest reliability of evoked BOLD signals from a cognitive–emotive fMRI test battery

    Neuroimage

    (2012)
  • I. Nouretdinov et al.

    Machine learning classification with confidence: Application of transductive conformal predictors to MRI-based diagnostic and prognostic markers in depression

    Neuroimage

    (2011)
  • Z. Wang et al.

    Support vector machine learning-based fMRI data group analysis

    Neuroimage

    (2007)
  • R.M. Hirschfeld et al.

    Bipolar disorder–costs and comorbidity

    Am J Manag Care

    (2005)
  • The Global Burden of Disease: 2004 Update

    (2008)
  • F.K. Goodwin et al.

    Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression

    (2007)
  • R.M. Hirschfeld et al.

    Perceptions and impact of bipolar disorder: How far have we really come?Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder

    J Clin Psychiatry

    (2003)
  • C. Baethge et al.

    Prophylaxis latency and outcome in bipolar disorders

    Can J Psychiatry

    (2003)
  • R.J. Baldessarini et al.

    Effects of treatment latency on response to maintenance treatment in manic-depressive disorders

    Bipolar Disord

    (2007)
  • R.H. Perlis et al.

    Transition to mania during treatment of bipolar depression

    Neuropsychopharmacology

    (2010)
  • M. Valenti et al.

    Risk factors for antidepressant-related switch to mania

    J Clin Psychiatry

    (2012)
  • R.J. Baldessarini et al.

    Morbidity in 303 first-episode bipolar I disorder patients

    Bipolar Disord

    (2010)
  • G.M. Goodwin

    Bipolar depression and treatment with antidepressants

    Br J Psychiatry

    (2012)
  • L.L. Judd et al.

    A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder

    Arch Gen Psychiatry

    (2003)
  • L.L. Judd et al.

    The long-term natural history of the weekly symptomatic status of bipolar I disorder

    Arch Gen Psychiatry

    (2002)
  • J. Angst et al.

    Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication

    Am J Psychiatry

    (2010)
  • H.S. Akiskal et al.

    Criteria for the “soft” bipolar spectrum: Treatment implications

    Psychopharmacol Bull

    (1987)
  • Cited by (203)

    View all citing articles on Scopus
    View full text