Two new family studies1,2 that demonstrate independent patterns of inheritance for mania and depression challenge the current conceptualization of bipolar mood disorder. The implications for genetic association and other neurobiological studies are profound.
Despite the vast investments in epidemiological, clinical and neurobiological research, the boundaries between the key psychiatric disorders remain indistinct. The pathophysiological paths that underpin the common affective disorders, including bipolar disorder, have not been clearly delineated.3 Consequently, choice of clinical treatments still occurs largely on the basis of reducing target symptoms (psychosis, depression, mania/hypomania and anxiety), resulting often in the use of multiple medical or psychological therapies.
These fundamental challenges are not simply advanced by the release of DSM-5 (http://www.dsm5.org/) or other new systems for use in research (for example, Research Domain Criteria of National Institute of Mental Health - http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml). Indeed, recent evidence from family, twin and molecular genetic studies highlight common genetic factors underlying schizophrenia and bipolar disorder.4 A specific area in which there is an urgent need for progress concerns the status of bipolar disorder. Given its shared features with unipolar major depression, psychotic depression, schizoaffective disorders and other psychotic disorders, some have concluded that it lies at the genuine interface of the affective and psychotic disorders.3 Recent modeling of large-scale molecular-based genetic data indicate the extent to which there appear to be common genetic risk factors to schizophrenia and bipolar disorder, schizophrenia and depression, and bipolar disorder and major depression.5
From an etiologic perspective, family-based (for example, familial inheritance, adoption and twin) studies have been the most robust method to determine not only the heritability of the major psychiatric disorders but also the extent to which common versus more specific (genetic or environmental) risk factors can explain familial aggregation of mental disorders. The extent to which specific phenotypes are repeated across generations (or co-occur with increasing evidence of genetic similarity) has been viewed as one of the strongest indicators of the neurobiological validity of a syndrome (for example, schizophrenia) or a key symptom construct (for example, mania). In fact, the currently accepted distinction between unipolar and bipolar depression draws heavily on earlier family study data.
The clinical concept of bipolar disorder is based on the notion that mania and depression are opposite ends of a single mood dimension—varying from elated to profoundly depressed states. An alternative conceptualization, recognizes increased activation as the core feature of mania and decreased activation as characteristic of some but not all depressed states. Critically, within this alternative model, the ‘bipolar’ dimension is one of motor and psychic activation, not mood. Consequently, it may vary from high to low states independently of mood. By contrast with current international classification systems, early descriptive studies considered mania and depression as distinct monopolar disorders. Population studies continue to demonstrate that manic episodes, particularly in the adolescent and early adult period, may occur independently of depressed mood.6 Ongoing research continues to provide evidence for differentiating those disorders characterized by mania (or activation states) from those principally characterized by depression (or low mood), with regards to longitudinal course, treatment outcome and premature mortality.7 However, the low prevalence of unipolar mania in clinical practice has led to diminished epidemiological or neurobiological assessments of this condition.
It is against this background that the two new family studies in this issue1,2 present further challenges to the current international classification systems, which underpin our key genetic, neurobiological and clinical studies. They provide strong evidence for characterizing subjects on a multidimensional matrix that rates mania (motor or psychic activation), major depression and psychotic syndromes as independent constructs. Specifically, the study by Merikangas et al.1 demonstrates the familial independence of mania from depression. This is consistent with the model in which bipolar disorder is characterized by a bidirectional ‘motor or psychic’ activation factor. That is, the activation factor may genuinely range from low (as seen clinically in melancholia, atypical depression, psychotic or bipolar depression) to high (as seen in mixed states, hypomania or genuine mania) (Figure 1). By contrast, depressed mood and psychotic features are both orthogonal in orientation and ‘unipolar’ in nature. When psychotic features are comorbid, the clinical states of psychotic depression or psychotic mania are observed. In this model, depressive symptoms are a common feature of all syndromes, and lack diagnostic specificity. Importantly, this model provides a more coherent explanation for ‘mixed states’ in which increased activation (or agitation) occurs concurrently with depressed or dysphoric mood.
The familial heritability of 0.83 for mania alone reported in the Merikangas et al.1 study closely approximates the 0.87 estimate of the Maudsley twin study of bipolar disorder.8 It strongly implicates genetic risk factors for mania (or activation) alone. The clear replication of the independence of mania and depression in the accompanying Lausanne Family Study2 suggests that the common findings from the two studies are not an artifact of unique methods, sampling structures or differential diagnostic practices. When taken together, the samples of the two studies include the full spectrum of mood and psychotic disorders from hospital, outpatient and community settings.
Importantly, the study of Vandeleur et al.2 also addresses the full spectrum of bipolar disorder, including its relationship with psychotic disorders. These findings from the Lausanne Family Study which demonstrate the comorbidity of psychosis and mania contradict those of earlier controlled family studies that demonstrated independence of familial aggregation of schizophrenia and bipolar disorder.9 However, the findings here of comorbidity between psychosis and ‘unipolar’ major depression emphasize that major depression is an important clinical phenomenon that should not be neglected in the evaluation of subjects with acute psychosis.
Interestingly, the origin of the key study hypothesis tested in these studies—namely, the potential to uncouple mania from depression was generated by the study of a US nationally representative sample of adolescents.6 It is consistent with those other epidemiological studies of affective disorders that have emphasized the spectrum of expression of mood, anxiety and other emotional phenomena and related these clinical characteristics to recurrence, course and stability in long-term prospective community samples. These newer family studies again demonstrate the importance of broader representation of the full spectrum of affective presentations as well as the active suspension of diagnostic criteria in the collection of phenotypes and subsequent analyses. With concomitant collection of relevant biomarkers, these ‘next-generation’ family studies will also provide valuable information on definitions of phenotypes and biological pathways underlying these disorders.
The apparent independence of the core domains underlying mood and psychotic disorders (that is, mania-activation, psychosis and depression) is actually in keeping with the widespread clinical practice of selecting therapeutic agents largely on the basis of symptom constructs (that is, antipsychotics for psychosis, antidepressants for depression, and mood stabilizers for mania). Likewise, the close link between schizoaffective disorders and schizophrenia with major depression in the Lausanne study also highlights the importance of concurrent depression in those with psychotic disorders.
Clinically, the most contested area of bipolar therapeutic research is the identification of efficacious treatments for ‘bipolar depression’. If subjects were defined for entry to this ‘entity’ by current evidence of ‘low activation’ (in addition to lifetime mania or hypomania), irrespective of current depression status, then a variety of stimulating or circadian-based agents may be more effective than other serotonin-based therapies. Within such a system, the current debate as to the nosological status of ‘mixed states’ would disappear, as those affected would not uncommonly experience both depressed mood and motor activation, indicating a need to treat the activation (for example, by lithium or other stabilizing agent) and the depressed mood (by antidepressant) as separate but clinically relevant conditions.
Future genetic and environmental risk studies, as well as clinical trials of relevant pharmacotherapuetic agents, may also benefit from use of a multi-axial system (Figure 1). That is, it may be more relevant to use continuous unidirectional measures of depression severity and psychotic symptoms, as well as bidirectional measures of motor or psychic activation, as the basis for selecting subjects for inclusion in studies or determining specific outcomes. From a bipolar perspective, much research would focus on selection according to activation state rather than current mood state. Further, the neurobiological mechanism underpinning the (bidirectional) ‘switch’ from low to high, or high to low, activation states would be highlighted. As this switch in activation is also linked to changes in the sleep–wake cycle, eating behavior and weight, a far greater emphasis may fall on circadian and other relevant brain and body clock mechanisms.10
Merikangas KR, Cui L, Heaton L, Nakamura E, Roca C, Ding J et al Independence of familial transmission of mania and depression: results of the NIMH family study of affective spectrum disorders. Mol Psychiatry advance online publication, 15 October 2013; doi:10.1038/mp.2013.116 (e-pub ahead of print).
Vandeleur CL, Merikangas KR, Strippoli M-PF, Castelao E, Preisig M . Specificity of psychosis, mania and major depression in a contemporary family study. Mol Psychiatry advance online publication, 15 October 2013; doi:10.1038/mp.2013.132 (e-pub ahead of print).
Goldberg DP, Andrews G, Hobbs MJ . Where should bipolar disorder appear in the meta-structure? Psychol Med 2009; 39: 2071–2081.
Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF et al Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234–239.
Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH et al Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.
Merikangas KR, Cui L, Kattan G, Carlson GA, Youngstrom EA, Angst J . Mania with and without depression in a community sample of U.S. adolescents. Arch Gen Psychiatry 2012; 69: 943–951.
Angst J, Hengartner MP, Gamma A, von Zerssen D, Angst F . Mortality of 403 patients with mood disorders 48 to 52 years after their psychiatric hospitalisation. Eur Arch Psychiatry Clin Neurosci 2013; 263: 425–434.
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A . The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497–502.
Maier W, Lichtermann D, Minges J, Hallmayer J, Heun R, Benkert O et al Continuity and discontinuity of affective disorders and schizophrenia: results of a controlled family study. Arch Gen Psychiatry 1993; 50: 871–883.
Hickie IB, Naismith SL, Robillard R, Scott EM, Hermens DF Manipulating the sleep-wake cycle and circadian rhythms to improve clinical management of major depression. BMC Medicine 2013; 11: 79.
IBH is a Senior Principal Research Fellow of the Australian National Health & Medical Research Council (AppID 1046899). He was a director of headspace: the National Youth Mental Health Foundation until January 2012. He is the executive director of the Brain and Mind Research Institute (BMRI), at the University of Sydney, which operates two early-intervention youth services under contract to headspace. He is a commissioner of the Australian National Mental Health commission and was previously the CEO of beyondblue: the National Depression Initiative. Previously, he has led a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs. He has led depression and other mental health research service evaluation or investigator-initiated research projects that have been supported by a variety of pharmaceutical partners. Current investigator-initiated studies are supported by Servier (manufacturers of Agomelatine) and Pfizer. He has received honoraria for his contributions to professional educational seminars related to depression, youth mental health and circadian-rhythms research. He has received travel support from Servier to attend scientific meetings related specifically to circadian-rhythm disorders.
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Hickie, I. Evidence for separate inheritance of mania and depression challenges current concepts of bipolar mood disorder. Mol Psychiatry 19, 153–155 (2014). https://doi.org/10.1038/mp.2013.173
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