Molly Murray

ISM

28 September 2018

Research Assessment 3

In his article about molecular psychiatry, I.B. Hickie assesses the evidence separate

inheritance of mania and depression in bipolar mood disorder. In essence, this article is

considering that mania and depression, the two defining factors of bipolar mood disorder, may

be two separate conditions. Unipolar depression, a factor opposite of that of bipolar depression

(which involves mania as well), is also discussed in this article to have many characteristics

parallel to those of psychotic disorders. This article utilizes a variety of previous case studies to

examine if unipolar depression and psychosis are concomitant and that bipolar depression and

mania may be less related than previously thought.

Bipolar disorder, often referred to as manic depression, is a mood disorder classified

by intervals of depression followed by a period of mania, in which individuals are generally

more “happy” and energetic. Hickie discusses that these these two, according to recent

researchers, many not be one disorder as so many believe it to be. There are certain “activation

states” that cause mania and depression, and while those for mania are considered to be a core

feature, that isn’t always the case for depressive states. Recent studies have shown mania to

occur without depression following, especially in teens and adolescents, but unipolar mania is

not common, thus there have been fewer assessments of this condition as its own disorder. I

began reading this article believing that while depression can be unipolar, mania is most

commonly found in bipolar disorder, along with depression. While there were definitely some
points that were made that almost convinced me, I maintain my previous thought, both mania

and depression come as a “package deal” in bipolar mood disorder.

Before reading this article, I had believed that mood disorders and psychotic disorders,

even anxiety disorders were in categories of mental health. My thoughts were that, while they

can coexist in one person, they are not genetically related. However, after reading this article, I

find myself believing that the connection between depression and psychosis are more connected

than I had previously believed. That being said, not every person that is clinically depressed is

psychotic and vice versa. However, a major factor that can be considered in psychosis is

depression, as some individuals with major depressive disorder may reach such a state of

depression, that they begin to experience symptoms of psychosis. The Lausanne study asserts

that schizophrenia and psychotic disorders both frequently involve concurrent depression.

I began reading this article thinking I would not agree, or really learn much for that

matter (I’ve got family with bipolar disorder). That, however, was not the case, and while I

definitely need some more convincing one separate hereditary of mania and depression, I have

learned that depression is an underlying disorder in many cases.

Evidence for separate inheritance of mania and depression challenges current
concepts of bipolar mood disorder
I.B. Hickie
Molecular Psychiatry.​ 19.2 (Feb. 2014): p153+.

Two new family studies (1,2) 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.

INTRODUCTION

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/researchpriorities/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 issue (1,2) 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 Study (2) 7suggests 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.

CLINICAL IMPLICATIONS

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.

RESEARCH IMPLICATIONS

Future genetic and environmental risk studies, as well as clinical trials of relevant
pharmacotherapeutic 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)

CONFLICT OF INTEREST

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 beyond blue: 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.