ACNP Meeting Highlights (cont.)

  The initial discovery of lithium’s neuroprotective and glial-protective mechanisms that potentially could account for some of these findings is the key to this new view. Dr. Muller-Oerlinghaussen and colleagues observed that patients appeared to be at increased risk of suicide if they discontinued their lithium, even if lithium had not been adequately effective in the prevention of their manic and depressive episodes. Although this finding was not systematically demonstrated in controlled studies, it fits with the new perspective on lithium’s protective action against neuronal and glial cell loss. In addition, this new data on lithium could help explain the observations that a number of other investigators have made, that if a patient discontinues their lithium, experiences a relapse, and then re-starts lithium, they are not always able to re-acquire the same degree of response that they first had on lithium.

  Initially, we had thought this was attributable to only the experience of a new episode of illness which, in some patients, could be enough to cause a change in the neurobiology of the illness such that it was less responsive to lithium. Given the new data at the ACNP meeting, a new set of possibilities arise. If lithium is indeed protective of neural and glial numbers and function, its removal may not only render the patient more likely to experience a clinical relapse, but it is now easy to conceptualize how there could be additional neurobiological insults to the CNS with the removal of lithium’s protective actions.

  Dr. Manji and colleagues has shown that acute administration of lithium increases gray matter in the brains of bipolar patients but not in normal volunteer controls. If lithium is normalizing the initial gray matter deficit experienced by many patients with bipolar illness or schizophrenia, it is possible that its removal could lead to a return to baseline hypofunction and theoretically further neuronal and glial loss if this hypofunction is an ongoing process that occurs over a person’s life span.

  Thus, with discontinuation of lithium resulting in as many depressive as manic episodes, it is possible that such depressions are associated with cortisol hypersecretion and alterations in a variety of other substances with the potential for adverse effects on neuronal and glial function and survival. A new set of stressors that emerge with illness re-activation as well as the biochemistry of the episode itself may thus increase the level of damage to an already vulnerable CNS.

 

IV.  Conclusions

  Thus, the new view from the ACNP meeting suggests the possibility that in stopping lithium treatment, one would not only have the potentially harmful effects of a new episode because of the increased likelihood of a relapse, but also the loss of lithium’s potential neuroprotective effects. It appears that it is the number of depressive (as opposed to manic) episodes that are associated with increased functional impairment and cognitive difficulties in bipolar illness. It is possible to view these data from the prospective that recurrent depressions are simply inherently more clinically incapacitating than manias. However, it is also possible to view this from the context that the increases in glucocorticoids that occur with depression potentially interact adversely with normal processes of age-related decline in glucocorticoid regulation (such as the inability of older individuals to rapidly terminate their acute stress responsivity at the level of glucocorticoid secretion), and thus increase neuropathology. The neurochemical alterations that occur with an episode could be increasing CNS vulnerability, and this process would be further accelerated in the absence of lithium’s protective effects.

  While these are hypothetical and theoretical processes, the empirical data themselves indicate that lithium has both positive effects in preventing suicide and reducing the excess medical mortality associated with depression.

 

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