The End of Anti-Depressants as We Know Them

November 26, 2013

 

How the future of antidepressants is diverging from its scattershot past

 

The End of Anti-Depressants as We Know Them

by Amy Maxmen

Sixty-one years ago, in a Staten Island hospital complex, doctors testing a new drug on tuberculosis patients observed a strange side effect: While the drug, known as an MAO inhibitor, was no miracle cure

for the hospital’s debilitated residents, it seemed to have an energizing, almost magical effect on their mood. One report noted that patients were “dancing in the halls tho’ there were holes in their lungs.’

The early history of what would come to be known as antidepressants is dominated by such stories of serendipity, and many pharmaceuticals prescribed for depression today are, by and large, descendents of these decades-old happy accidents. Newer drugs replaced old ones because they were safer, not more effective, explains William Potter, senior advisor to the director of the National Institute of Mental Health.

Now, as psychiatry inches toward a more refined understanding of the neurochemistry of depression, the course of drug discovery is changing. Roughly half of all clinically depressed patients fail to respond to available antidepressants-all of which target one neurotransmitter or another-and the lack of relief provides an important clue: Depression is not a monolithic disease, but a set of symptoms that can spring from a variety of causes. A treatment may work, scientists are finding, only when it is tailored to the type of depression found in a particular patient. “Today’s antidepressants seem to change the brain only slowly and indirectly,” explains Olivier Berton, a neuroscientist at the University of Pennsylvania.

How the future of antidepressants is diverging from its scattershot past

Because doctors knew that some early antidepressants boosted serotonin, they hypothesized that the neurotransmitter may be linked to depression. But a person’s outlook doesn’t start to shift until a month after beginning serotonin-altering drugs like Prozac, even when they work. The delay suggests another process is involved. Enter neural plasticity. Researchers have long observed the growth of new brain cells following antidepressant use. It may be that the sluggishness and stunted outlook that characterize depression at bottom  reflect a failure to generate  new nerve cells, and yet the role of serotonin in neurogenesis is indirect, at best. The chain of reactions that link them remains largely unknown.

Recently, however, new research has begun to point to substances in the brain that act closer to the scene of neurogenesis, suggesting  more logical drug targets.  In June, researchers reported one important step in Nature Medicine. After mice took Prozac-Iike antidepressants, the levels of a fat molecule in the brain called ceramide plummeted.  Ceramide normally stalls brain cell growth;  by blocking ceramide, the drugs presumably  jump-started  neural regeneration.  New drugs that inhibit ceramide  could  work  faster than  drugs that  act on serotonin   because  they  are more directly linked to neurogenesis, the authors suggest.

Others   are  entirely    abandoning approaches related to serotonin. Researchers know that individuals who are obese or who take immune-altering   medications may not respond to antidepressants. What such people have in common  is chronic inflammation,  explains Emory University psychiatrist Andrew  Miller. He believes that inflammation   is a particular  path to depression  that  stems from  a beneficial adaptation. Depression is often characterized by what are called sickness behaviors – withdrawal  from others, loss of appetite, lethargy.  These are typical  responses  to physical  injury  and infection, and, in the short term, may foster recovery. Such responses become a problem, Miller says, only when the inflammation   is chronic. Then the depressive behavior endures.

Earlier this year, Miller investigated whether a drug  currently used to tame inflammation in rheumatoid arthritis might  help people  who found  no relief in antidepressants   and failed to respond to talk therapy. The drug indeed  helped depressed patients with excess inflammation and did little for those without.

Depression  that stems from trauma can  also be especially resistant   to conventional    antidepressants. Scientists believe that trauma  may cause epigenetic changes-lastingly modifying molecules that  turn  mood-  and  behavior-related genes on or off. The upshot  may be that those who experience trauma early in life may be unable to bounce back from later hardship the way other people can.

Penn’s   Berton  recently studied trauma-induced depression in  mice. Bullying – one type  of trauma, easily modeled  in animals – typically causes a meeker mouse to act asocial, refrain from favored foods, and scare easily-behaviors analogous to those of depressed humans. But when Berton blocked a particular protein in the bullied  mice, they showed no such symptoms.  Berton  is now collaborating  with  a pharmaceutical  company to develop  a drug  that  blocks  the same protein. Other researchers are also experimenting  with drugs that block different proteins that may act as on/off switches for the genes affected by trauma.

“For  a long  time,  people  focused only  on serotonin,   and  that  inhibited new avenues  of investigation,” Berton says.  Now that the variety of mechanisms underlying depression is becoming clearer, a one-size-fits-all approach may soon be a thing of the past.

(article originally published at Psychology Today – Nov/Dec 2013)