Wednesday, May 1, 2013

BDNF Theory of Depression

Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation. Like other drugs of its class such as tiletamine and phencyclidine (PCP), it induces a state referred to as "dissociative anesthesia" and is sometime misused as a recreational drug.

Uncovering the Biology of Depression

by Jonathan Hwang, Yale Scientific, 2011

Professor of Psychiatry and Pharmacology Director at Yale University, Ronald Duman studies depression, a serious issue that affects approximately 17% of the U.S. population and is estimated to cost as much as $83.1 billion for our economy.

There is a general consensus in the scientific community that low levels of monoamine neurotransmitters are a major contributor of depression. From that belief, antidepressants are designed to increase levels of neurotransmitters in the brain. They block reuptake or breakdown of different types of neurotransmitters in order to maintain higher levels in the brain.

A diverse range of antidepressants exists. However, current antidepressants are still ineffective and have low response rates: only 1 in 3 respond to the first antidepressant treatment, and 2 in 3 ever respond after repeated treatments. Beyond knowing that antidepressants block or inhibit particular neurotransmitters, most scientists are still not sure which pathways these antidepressants influence and thus the types of mechanisms that contribute to depression. Duman’s work investigates these unknown pathways.

Neurotrophic Theory of Depression

The bulk of Professor Duman’s research has led to the formulation of the neurotrophic theory of depression, which states that neuronal growth factors contribute to the onset of depression. In 1995, Duman published a landmark paper relating increased brain derived neurotrophic factor (BDNF) levels with antidepressant effects, setting the foundation for the neurotrophic hypothesis of depression.

Since then, subsequent research has clarified the pathways leading to the expression of BDNF. Professor Duman’s research suggests that BDNF is expressed through the cyclic adenosine monophosphate (cAMP) signal transduction pathway, which is regulated by serotonin.

In this pathway, cAMP is first activated, and this leads to activation of cAMP dependent protein kinase, which regulates cAMP response to element-binding protein (CREB). Additionally, Duman found that long-term antidepressants increase levels of CREB mRNA and protein in the hippocampus, further supporting the link between antidepressants and the cAMP pathway. CREB seems to regulate a set of genes in the hippocampus producing antidepressant effects.

Stress reduces the complexity of density of dendrites (top) as compared to normal dendrites (bottom). Image courtesy of Duman.

The Role of BDNF

BDNF is a vital neurotrophic factor in the brain. Previous studies have shown that exposure to BDNF in the hippocampus can lead to increased strength in some synaptic connections. BDNF’s role in neurogenesis was of particular interest. Duman discovered that upregulation of neurogenesis was the result of several antidepressants, suggesting that antidepressants reverse the atrophy of neurons that occur during depression.

Other studies confirming Dr. Duman’s work have found that increasing levels of BDNF in specific areas of the brain, such as the hippocampus, leads to antidepressant effects. The hippocampus has been implicated in mood disorders and its connections to amygdala and the prefrontal cortex are important for the function of cognition and emotion. Additionally, studies by Duman also revealed the converse: loss of BDNF contributes to depression. Stress, a precursor of many mood disorders, also decreases expression of BDNF.

The approaches Professor Duman took to clarify BDNF’s role were varied. One was by using a viral vector to overexpress BDNF, which produced a behavioral phenotype typical of antidepressants. Antidepressant behavior was tested using the forced swim tests and learned helplessness models.

Another approach involved infusing recombinant BDNF into the brain region, which also produced a
similar antidepressant behavioral response. Duman also tested mice with a heterozygous deletion of the allele for BDNF. Although their phenotype appeared normal, they displayed a depressant-like phenotype once exposed to stress. This follows the widely held belief that a combination of environmental and genetic factors contributes to the onset of depression.

The mechanism regulating the expression of BDNF. Image courtesy of Duman.

A Faster and More Efficient Pathway

In August 2010, Duman’s lab discovered a completely new pathway, a major breakthrough for the field of depression. In ketamine, Duman addresses a pressing need in the field for “a more rapid, more efficient drug” to treat depression. In his paper published in Science, Duman lays the foundation for further understanding of this novel pathway.

Ten years ago, ketamine was preliminarily tested at the Connecticut Mental Health Center as an antidepressant in low doses. The subjects were patients who previously resisted all other forms of treatment, but over two thirds responded positively to ketamine. These results were confirmed in later studies. Much more remarkable about ketamine’s use as an antidepressant was how quickly the patients responded; antidepressant effects took place within two hours of treatment and lasted more than seven days.

“The story is in the pathway,” Duman explained. Unlike traditional antidepressants, which are generally neurotransmitter inhibitors, ketamine is a N-methyl-D-aspartic acid (NMDA) receptor antagonist.

It operates on an entirely different pathway from those of traditional neurotransmitters. Studies conducted by graduate student Nick Li demonstrate that ketamine activates the mammalian target of rapamycin (mTor) pathway. mTor is a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity in a process called synaptogenesis.

Synaptogenesis restores the synapse connections in the brain that may deteriorate under stress and depression. The study also found increases in the levels of synapse proteins usually regulated by the mTor pathway. To physically confirm synapse formation, in collaboration with George Aghajanian, Professor of Psychiatry at Yale, two-photon imaging was used to observe increased spine density. Further supporting the link between the mTor pathway and antidepressant effects, Duman blocked the mTor pathway with rapamycin, leading to inhibition of ketamine’s antidepressant effects.

Ketamine is such a “magic drug” because it produces antidepressant effects in people who have resisted most other forms of treatment and its speed of response acts in days rather than weeks.

However, the key disadvantages of directly using ketamine as an antidepressant are its use as a street drug and its toxicity from repeated dosages. Despite these shortcomings, knowing the mechanisms of ketamine’s antidepressant effects will further benefit drug designs for immediate antidepressant effects.

Duman’s lab continues to further investigate factors and pathways for depression. One future direction is to deepen understanding of what stress does on a molecular scale and its link to depression. Other directions include studies to reveal more details about the mechanisms underlying Duman’s neurotrophic theory of depression. Professor Duman’s discoveries today could be the basis of depression treatments tomorrow.

Two-photon microscopy of neurons after treatment with ketamine (bottom) as compared to control (top) shows increased density. Image courtesy of Duman and Aghajanian.

About the Author

Jonathan Hwang is a Chemical Engineering major in Saybrook College.

The author would like to thank Professor Ronald Duman for his time and assistance over the course of writing this article.

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