Do SSRI's Even Work? And if so, How?

Just in case you feel like reading Sunday's New York Times Magazine before it come out, over on "Post-Prozac Nation: The Science and History of Depression," Siddhartha Mukherjee will be writing about the history and efficacy of antidepressants.  Dr. Mukherjee writes:


Fast forward to 2012 and the same antidepressants that inspired such enthusiasm have become the new villains of modern psychopharmacology — overhyped, overprescribed chemicals, symptomatic of a pill-happy culture searching for quick fixes for complex mental problems. In “The Emperor’s New Drugs,” the psychologist Irving Kirsch asserted that antidepressants work no better than sugar pills and that the clinical effectiveness of the drugs is, largely, a myth. If the lodestone book of the 1990s was Peter Kramer’s near-ecstatic testimonial, “Listening to Prozac,” then the book of the 2000s is David Healy’s “Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression.”


He talks about depressed people in the 1950's being cured as a side effect of their treatment for tuberculosis (isoniazid was one of the first medicines to elevate mood in the depressed) and hyptertensive patients becoming depressed on Raudixin.


Mukherjee goes on:

In 2011, Hen and his colleagues repeated these studies with depressed primates. In monkeys, chronic stress produces a syndrome with symptoms remarkably similar to some forms of human depression. Even more strikingly than mice, stressed monkeys lose interest in pleasure and become lethargic. When Hen measured neuron birth in the hippocampi in depressed monkeys, it was low. When he gave the monkeys antidepressants, the depressed symptoms abated and neuron birth resumed. Blocking the growth of nerve cells made Prozac ineffective.

Hen’s experiments have profound implications for psychiatry and psychology. Antidepressants like Prozac and Zoloft, Hen suggested, may transiently increase serotonin in the brain, but their effect is seen only when new neurons are born. Might depression be precipitated by the death of neurons in certain parts of the brain?


He finishes off with the ideas:

The differences in responses to these drugs could also be due to variations in biological pathways. In some people, neurotransmitters other than serotonin may be involved; in yet others, there may be alterations in the brain caused by biological factors that are not neurotransmitters; in yet others, there may be no identifiable chemical or biological factors at all. The depression associated with Parkinson’s disease, for instance, seems to have little to do with serotonin. Postpartum depression is such a distinct syndrome that it is hard to imagine that neurotransmitters or hippocampal neurogenesis play a primary role in it. 

Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. It is very unlikely that we can “talk” our brains into growing cells. But perhaps talking alters the way that nerve death is registered by the conscious parts of the brain. Or talking could release other chemicals, opening up parallel pathways of nerve-cell growth. 

But the most profound implications have to do with how to understand the link between the growth of neurons, the changes in mood and the alteration of behavior. Perhaps antidepressants like Prozac and Paxil primarily alter behavioral circuits in the brain — particularly the circuits deep in the hippocampus where memories and learned behaviors are stored and organized — and consequently change mood.