Can Regret Help Identify Mood Disorders?

Decision-Making Dysfunctions of Counterfactuals in Depression: Who Might I Have Been?

Howlett JR, Paulus MP
Front Psychiatry. 2013;4:143

Mood Disorders

Disorders of mood -- be they unipolar, bipolar, or found within the spectrum from euthymia to dysphoria -- are pervasive, unrelenting, and, if looked at from an epidemiologic perspective, a modern-day plague. The suffering is unrelenting, and it kills. Prospective and retrospective studies point to 13% of adults contemplating suicide, with 4.6% making a serious attempt.^[1] From 78% to 89% of suicide attempters and completers with a history of a mood disorder do so while in the middle of a depressive episode.^[1] This is clearly an emergency; therefore, better ways of recognizing when sadness and despondency might be abnormal are of paramount importance in saving lives.

Phenomenologic "Observation" vs Biological Markers

By way of exquisite long-term observation of mood-disordered patients, the German psychiatrist Emil Kraepelin was able to tease apart those whose mood fluctuated and exhibited cognitive disturbances when in the acute phase of the illness (manic-depressive insanity) from those with a deteriorating course (dementia praecox). In the more than 100 years after his initial observations, multiple prospective observational and retrospective studies have validated Kraepelin's initial observation,^[2] and the discovery and use of pharmacologic options (such as lithium), after proper diagnosis, has had a huge positive impact on treatment.^[3]

Nevertheless, the current expanded diagnostic nosology based on overlapping Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria has made it ever more difficult to properly adjudicate symptoms and separate diagnoses. The symptom of depression, for instance, is not only many times adjudicated to the wrong diagnosis, but more times than not it is missed altogether. Careful observation, in the absence of the burgeoning neuroscientific data we now possess, led Dr. Kraepelin to gigantic insights into diagnosis. Today, however, misdiagnosis and missed diagnoses of severe depression, the topic of this commentary, are unnecessarily rampant. An alternative route to that of careful observation has entailed trying to come up with mechanistic explanations for mood disorders -- that is, to elucidate what might be happening at the neuronal and circuit level in the brain of depressed individuals.

Notwithstanding the array of discoveries in the neurosciences, overlap of biological endophenotypes across current DSM diagnoses, such as DSM symptom overlap across diagnoses, remains very common. The story of corticotrophin-releasing factor/hormone (CRF/H) and its relationship to anxiety and depressive disorders is but one example. Detailed explanations of the effects of CRF/H on catecholamine neurotransmission (serotonin, dopamine, and norepinephrine) and the genesis of depression and anxiety^[4] are explanatory from a neurobiological perspective, yet its dysfunction has been observed in unipolar and bipolar mood disorders and in some of the different DSM anxiety disorders. Given that depression and anxiety might have a common origin at the genetic and circuit levels,^[5,6] it is not surprising that such markers as CRH/F will not be specific for alternative DSM diagnoses. Yet, at the randomized clinical trial level (the highest level of evidence in evidence-based medicine), differences exist when applying pharmacotherapeutic agents to some of the anxiety disorders vs the mood disorders. "Measuring" CRF/H levels in patients with major depression or generalized anxiety disorder could potentially yield similar values in both disorders,^[7,8,9,10] thereby still making it difficult to differentiate one psychiatric disorder from the other.

To that extent, from a nosologic perspective, detailed description of CRF/H system dysfunction in "depression" as a symptom/diagnostic endophenotype is perhaps of little clinical value insofar as it doesn't point to a particular diagnosis (eg, major depressive disorder, bipolar disorder, or generalized anxiety disorder) among other mood and anxiety disorders. On the other hand, findings of a common dysfunctional CRF/H system in disorders of mood and anxiety could be slowly leading us to a new way of conceptualizing nosology by allowing us to understand that artificial diagnostic entities are of no real clinical value.^[11] In the "real world" of clinical psychiatry, however, some guidance is needed if clinicians are to properly diagnose and treat psychiatric patients. In the absence of valid, reliable, and even practical biological markers, the clinician needs another type of reliable endophenotype that allows for appropriate diagnosis and, in the case of this commentary, prevents the clinician from missing a serious evolving depression. This is precisely where Howlett's article is of help.

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