A Look at Psychopharmacology and Theories of Depression

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Prozac pillsWe now believe that depression is in part a biochemical event. This theory did not come from nowhere – rather it comes from just 60 years of experimenting with medications that had biochemical effects.

But at the same time as we have learned that depression is, indeed, in part biochemical, the limitations of medications remind us how little we ultimately know.

It all started when patients being treated for tuberculosis by various experimental treatments started feeling really, really good. Researchers wondered what was going on.  Careful investigation showed that  the treatment being given to them had potent antidepressant action.

This led to the class of medications known as MAO inhibitors. These drugs work on the monoamine oxidase system, inhibiting it.  Because this pathway degrades important neurochemicals, inhibiting it increases their levels, which seems to work to improve mood.

Those medications worked well but they had serious side effects.  The MAO system is also used to take care of degrading tyramine.  Consuming food or drink high in tyramine, like cheese or red wine, could lead to a potentially fatal hypertensive crisis.

But the fact that a medication working purely on a chemical level could improve someone’s mood was game-changing. It meant that maybe it was something going on at a chemical level that led to depression.

The next round of depression medications was the tricyclic antidepressants (TCA).  They were fairly effective and we still have not surpassed them for efficacy in terms of medication.  The key concern with the TCA was their potential for significant side effects.  While not as serious as with the MAO inhibitors, they could cause heart problems, especially in an overdose situation.

By further refining the biochemical action, we developed the selective serotonin reuptake inhibitors (SSRIs). The SSRIs work almost only on the neurotransmitter serotonin.  They work well, albeit possibly a very, very little less than the TCA, and, most importantly, were significantly safer.  An overdose is rarely fatal, always a concern with people who are seriously depressed.

The rise of the SSRIs led to the widespread belief that serotonin was the main neurotransmitter associated with depression.  At the same time, however, as this was the developing theory, challenges began to arise.  Importantly, medications that worked as antidepressants but that did not have serotonin effects directly, like Wellbutrin, were developed – and worked just as well as the SSRIs.

Additionally, research began to indicate that directly lowering or increasing levels of serotonin did not affect mood.  So someone who is given low levels of serotonin in the lab won’t necessarily report feeling rotten, and someone whose levels are raised, won’t necessarily feel great.

Further challenging the simple “low levels of serotonin cause depression” model was this. While the effects of an SSRI were biochemically taking place within a day of starting treatment, serotonin levels quickly went up, it takes several weeks for the effect to fully develop.

This has led in part to the growing theory of neurogenesis. This theory holds that antidepressants primarily work by stimulating certain parts of the brain to grow and develop connections with other brain cells. Antidepressants, then, work to promote a more networked, active brain.

The main downside to this theory is that it is not as easily summarized or memorable, but it does seem to be emerging as the dominant theory.

Future development of antidepressants is exciting and remains open. A variety of chemical targets are emerging as being important in future treatments.  Recently, a growing amount of serotonin norepinephrine reuptake inhibitors (SNRI) medications have gone to market. They may work faster than the SSRIs.  And novel therapies are being developed that may or may not have serotonin effects.  The new antidepressant Valdoxan, for instance, works primarily on melatonin.

But even with what we’ve learned about depression from the medications that treat it – there is a significant limitation. In some studies, antidepressants don’t work much better than placebo. And even in the studies where they work best, there is still only about a 66% response rate.

These limitations must remind us that as humans, we somehow transcend just the biochemical.

About the author:

David loves blogging about health and medical issues!  Recent work he has done includes writing an analysis of normal blood pressure ranges in adults, which discusses what the issues around blood pressure are.  And even more recently, he analyzed glucosamine & chondroitin as a treatment for arthritis.