How Illness Progresses In The Recurrent Affective Disorders

December 12, 2012 · Posted in Peer-Reviewed Published Data, Risk Factors 

depressed man with woman

This editor (RM Post) in collaboration with Jacqueline Fleming and Flavio Kapczinski published the article “Neurobiological mechanisms of illness progression in the recurrent affective disorders” in the Journal of Psychiatric Research this year. The article built on several themes about the progression of bipolar illness that had been explored in previous research.

These themes include:

  1. The likely acceleration of repeated episodes as a function of the number of prior episodes (episode sensitization)
  2. The increased responsivity of the illness to repeated stressors (stress sensitization)
  3. The increased behavioral reactivity to repeated use of psychomotor stimulants such as cocaine (stimulant-induced behavioral sensitization)

Not only are these observations well documented in the scientific literature, but recent observations also suggest that each type of sensitization can show cross-sensitization to the other two types. That is, individuals exposed to repeated stressors are more likely both to experience affective illness episodes and to adopt comorbid substance abuse. In a similar way, episodes of an affective disorder and stressors may also be associated with the relapse into drug administration in those who have been abstinent.

In addition to these mechanisms of illness progression in the recurrent affective disorders, the new article reviews the literature showing that the number of affective episodes or the duration of the illness appear to be associated with a variety of other clinical and neurobiological variables.

The number of affective episodes a patient experiences is associated with the degree of cognitive dysfunction present in their bipolar illness, and experiencing more than 4 episodes of unipolar or bipolar depression is a risk factor for dementia in late life. A relative lack of response to most treatments is also correlated with the number of prior episodes, and this holds true for response to naturalistic treatment in general. While most of these data are correlational and the direction of causality cannot be ascertained for certain, it is likely that the number of affective episodes and/or their duration could account for and drive difficulties with treatment and with cognitive function.

If this were the case, one would expect to see a variety of neurobiological correlates with the number of prior episodes or duration of illness, and in the article we summarize those that have been found in unipolar and bipolar disorder. Considerable data indicate that cortical volume and degrees of prefrontal cortical dysfunction can vary as a function of number of prior episodes. There is evidence that increased activity of the amygdala and the nucleus accumbens are also related to episodes or duration of illness. In those with unipolar depression, the volume of the hippocampus is decreased with longer duration of illness.

Some inflammatory markers also increase as a function of number of episodes or duration of illness, and recent studies have indicated that patients with bipolar disorder and other serious mental disorders have shorter life expectancies than the general population, based largely on increases in cardiovascular-related illnesses.

The ratio of short to long telomeres (the segment of DNA at the end of each chromosome), which increases as a function of aging, is significantly higher in bipolar II depressed patients as a function of number of prior depressive episodes. This increase in short telomeres is equivalent to approximately 10 years of premature aging. Stress and its downstream effects on cortisol and other stress hormones as well as inflammatory processes could result in this increased proportion of short chromosomes, but the pathophysiological mechanisms by which this occurs in bipolar II depressed patients have not yet been identified.

There are many reasons why numbers of episodes of depression could relate to degree of neurobiological abnormality, based on the findings that each episode of depression is associated with increases in inflammatory factors and oxidative stress and the production of free radicals, as well as decreases in neuroprotective factors such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF).

Recurrent episodes may increase the number of factors toxic to neurons and glial cells in the relative absence of neuroprotective factors. This would provide a plausible set of mechanisms to explain the relationship of number of episodes to brain and somatic system abnormalities. However, it again must be cautioned that it is also possible that greater degrees of these abnormalities are associated with a greater vulnerability to episode recurrence, and the direction of causality remains to be further ascertained.

Nonetheless, preventing episodes is a goal that has considerable merit in its own right, as this would decrease the suffering and dysfunction associated with manic and depressive episodes even if it did not mitigate the neurobiological abnormalities and slow the progressive course of the affective disorder.

Thus the clinical message of this research into illness progression is that there is a great need for early intervention and long-term prevention in the recurrent affective disorders, to prevent morbidity and mortality from these illnesses, but also to lessen the risk of illness progression and deterioration. Prevent episodes, protect the brain is our new motto.


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