Bipolar Disorder: What’s Known and What’s Next

Stress is a key risk factor

Posted Jan 03, 2012

Bipolar disorder is currently believed to arise from interactions between the classic two forces that drive most of our biology: the genetic risk factors we inherited from our parents and the consequences of our environment.   It is now clear that unpleasant events during childhood that lead to chronic stress and or mental and physical trauma also contribute to the appearance of symptoms later in life.  Studies using both MRI scans and postmortem investigations indicate that if adverse experiences occur during critical developmental periods that actual structural and functional changes develop in the brain; these changes may have long-lasting effects on adult brain function. Furthermore, developmental errors in brain wiring can be aggravated or unmasked later in life by exposure to stressful events.  Clearly, stress is a key risk factor in the appearance of bipolar symptoms.

Bipolar disorder is not due to a specific lesion or degeneration in a single part of the brain.  It is a collection of symptoms that represent a disruption in how multiple brain regions talk to each other.  There is an error in how some brain regions wired themselves together during development that make some people susceptibility to bipolar disorder.  As a consequence of these wiring problems some brain regions are too small and some areas of cortex are too thin. 

Bipolar disorder is characterized by severe bouts of repeated mania and depression.  The phenomenon of switching between depression and mania is what truly distinguishes bipolar disorder from other psychiatric disorders.  This switching can occur spontaneously but can also be influenced by exposure to stress, sleep deprivation and some illicit drugs.  One recent study identified a group of patients who all developed bipolar disorder symptoms after using of cocaine.  Ironically, the therapies administered to help these patients actually will induce the switching from depression into mania, such as electroconvulsive shock therapy, antipsychotics and some antidepressants, particularly those drugs that target serotonin and norepinephrine.   When injected into susceptible people, stress hormones can induce both manic and depressive episodes.  

Scientists now realize that a better understanding of this switching process is essential because individuals with faster rates of switching have a poorer clinical outlook and carry greater risk for substance abuse and suicide.   Unfortunately, no one has yet identified a specific biomarker or gene that can reliably diagnose bipolar disorder.  

The complexity of the underlying problem is why there is such a wide array of drug treatments for patients with bipolar disorder.  They are known collectively as mood-stabilizing drugs and include lithium salts and the anticonvulsants valproate, carbamazepine and lamotrigine.  All of these drugs reduce the symptoms of mania and some, such as lithium and lamotrigine, have well known antidepressant effects.  In general, lithium treatment alone is often insufficient, and the majority of patients are given a combination therapy of these and other drugs.  Unfortunately, many patients cannot tolerate the unpleasant side effects, including changes in weight and appetite, tremor, blurred vision, metallic tastes and dizziness.

Obviously, treatments that are more effective, act faster and are better tolerated are badly needed, not only because the currently available ones are not terribly effective and have numerous side-effects that limit their efficacy, but also because bipolar disorder is so very common, with approximately 1% of the population affected and because these patients are prone to cardiovascular disease, diabetes mellitus and thyroid dysfunction. 

Today, much more is known about how lithium acts within the brain.  This knowledge has moved the focus away from the classical mood-related neurotransmitters dopamine, norepinephrine and serotonin, to alterations in the function of the neurotransmitter glutamate and the role it plays in regulating neurogenesis in the hippocampus.  Neurogenesis is the birth of new neurons that occurs throughout life, particularly within the hippocampus - a brain region vital for controlling both learning and memory and our response to stress.   Lithium can actually enhance neurogenesis and improve the resiliency of brain cells in the presence of stress hormones.  Long term treatment with lithium may even slow the onset of Alzheimer's disease.  

Newer classes of drugs that modulate the action of glutamate are now being actively investigated.  For example, one exciting finding last year was that the street drug ketamine can exhibit a very fast-acting antidepressant effect; however, there are significant concerns about its long term safety and effectiveness.  In addition, a recent report in the Archives of General Psychiatry claimed that deep brain stimulation, similar to that used on patients with Parkinson's disease, might be quite effective for patients with bipolar disorder. 

© Gary L. Wenk, Ph.D. Author of Your Brain on Food (Oxford, 2010)

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