The SSRI Problem: Moving Past Monoamines

Selective Serotonin Reuptake Inhibitors have been the first-line treatment for depression for over two decades, with the introduction of Prozac, which often gets the credit as the first SSRI, though it was merely the first marketed SSRI, not the first discovered SSRI (zimelidine holds that honor), it still holds the title as the drug that revolutionized psychopharmacological treatment of depression and, twenty years later, other disorders such as anxiety, panic disorder, obsessive-compulsive disorder and others. SSRIs have a modest side effect profile (though not too modest, as we will see), and produce symptom relief in about 55-60% of patients, an acceptable, though not stellar, efficacy profile.

The scientific development that led to SSRIs was the monoamine hypothesis; original antidepressants such as monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were discovered (accidentally) in the 1950s, and were known to increase levels of serotonin, norepinephrine and dopamine in the brain. Researchers found that the earliest antidepressants, which were being developed for other purposes, had antidepressant properties; conversely, they found that drugs that reduced monoamine levels actually had pro-depressive effects. This led to an influential paper pubished in 165, "The Catecholamine Hypothesis of Affective Disorders." The discovery of the monoaminergic mechanisms of these older drugs led to a targeted effort to find newer, safer and more targeted treatments: introducing the SSRIs.

Moving forward to today's research, SSRIs have some issues that need to be addressed, and indeed they are, albeit slowly. Despite this evidence, for example, SSRIs take anywhere from four to six weeks to take effect, despite the fact that the actions they have on serotonin levels takes effect within days of drug administration, not weeks. Additionally, there haven't been any studies - absolutely none - demonstrating that levels of serotonin are actually low in people with depression (either pre or postmortem studies). What this indicates, and neuroscientists are tending to agree, is that the action of SSRI antidepressants are not actually related to the increased serotonin levels, but to more long-lasting downstream effects on a receptor type known as the NMDA receptor - N-methyl D-aspartate - receptor type in the glutamate system. It is believed that SSRIs act toward the beginning of a series of effects that leads to this receptor system being activated, with end results such as hippocampal neurogenesis (the growth of new neurons in the hippocampus). It is these and other downstream actions that appear to produce symptom reduction.

This seems to be good news for people on SSRIs; despite their relative safety, they still have issues that should be discussed. SSRI discontinuation syndrome, for example, is a growing problem issue and is increasingly being recognized by psychiatry as an actual diagnosis resulting from abrupt (or even tapered) discontinuation of SSRIs. This syndrome is very uncomfortable, with symptoms such as nausea, emesis, crying spells, anxiety, headaches, confusion and sleeping disturbances. The discontinuation can mimic the symptoms of a relapse, which may lead to restarting the drug based upon faulty reasoning.

Another issue with SSRIs is one of emotional blunting; what this means is that people on these medications not only have less negative emotions, such as those associated with the actual depressive disorder, but also fewer positive emotions, as well. This is never a good thing for depressed patients, since a lack of positive affect leads to less reinforcement, which can ultimately reinforce depressive thinking and anhedonia; it is especially problematic for people with minor or transient depressive symptoms, for which SSRIs are often wrongly prescribed. For these patients, positive emotional experiences and reinforcement are important in their recovery, especially in the absence of the most severe symptoms seen in major depression. The final issue I will address briefly is one of residual symptoms; SSRIs tend to leave behind some symptoms of depression, especially somatic symptoms such as fatigue. These residual symptoms can lead to higher relapse rates and certainly a reduced quality of life than if they were being appropriately treated. Adjunctive pharmacotherapy is sometimes used for treating residual somatic symptoms, drugs such as atomoxetine, modafinil, or buproprion, which are relatively effective for this purpose.

There is a clear line of research that is attempting to move past the monoamine hypothesis, which has lost much of its credibility for reasons discussed above, towards newer, more targeted treatments. This line of research isn't actually producing any novel medications yet; the newer drugs that have been released for depression, such as desvenlafaxine, duloxetine and escitalopram, are all recapitualations of the SSRIs and SNRIs (which act on both serotonin and norepinephrine) with no clear benefits over currently available medications. In fact, desvenlafaxine and escitalopram are simply S-isomers of two older drugs, venlafaxine and citalopram, respectively. What this means is that they are synthetic versions of the products are bodies make from the parent compounds; they work the same way as the parent compounds with few clear benefits.

The benefits of having new medications that act further down the cascade of reactions discussed above are theoretical at this point, but we will speculate on their benefits. One clear benefit would be fewer side effects; the vast majority of the side effects of SSRIs and SNRIs are a direct result of the increased monoamines in the synapse, despite the fact that the increased monoamines have little to do with the efficacy of the drug. A more targeted drug that acts directly on NMDA receptors and neurogenesis in the hippocampus could theoretically eliminate most of the side effects, including the emotional blunting and discontinuation syndromes discussed previously. This increased targeting could also result in our treatments being more transient than they currently are; it isn't uncommon for people to be on SSRIs for their entire lives. Newer targeted drugs working more potently downstream in the brain may (though this is speculative) not require life-long medication.

Either way it is clear that the psychiatric community's love affair with SSRIs is, in some regards, misplaced. These medications are certainly the safest effective treatments we have for these disorders, but they are prescribed too readily and postremission assessments (taking people off the drug after remission) is all but unheard of because of the high relapse rates. People are given SSRIs for subclinical depression and transient depressive symptoms, which is a problem especially given the issues outlined above with discontinuation and emotional blunting. While it is difficult to say when a new class of antidepressant will ecclipse SSRIs and SNRIs, the research is being done and, with any luck, we'll have more targeted treatments within the next couple of decades.

Comments

[Rich Palmer]

While I do tend to agree with much of what you said, especially in regards to overprescribing and some of the side effect issues, you do kind of imply that there is another option on the table that is already more targeted and already works on the mechanisms you describe.

I know your argument is in regards to focusing our research in the field, but you make an issue against SSRIs in clinical practice when, unfortunately, there aren't good alternatives available yet.

Despite that, your points are quite valid in regards to SSRIs not being absolutely perfect.

[Greg Hard]

Thanks, Rich, for your feedback. My point was to argue against the use of SSRIs for anything other than severe psychopathology given the issues I discussed (discontinuation, emotional blunting, etc). They are often touted as being "uber-drugs" and I wanted to outline issues with the move that psychiatry seems to be making towards complacency with our current imperfect (though beneficial, undoubtedly) treatments, and that includes prescribing them like candy to individuals who could benefit from CBT, IPT or other treatments for their subsyndromal issues.

I did try to make it clear that SSRIs and SNRIs are absolutely first-line treatment for severe psychopathology. This isn't to say that research shouldn't be principally directed towards the newer theories I outlined, to produce a better class of drug to replace SSRIs in the future.

Thanks for your feedback!

Greg