During my residency days Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine (Prozac, Sarafem), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and sertraline (Zoloft), were pushed as being better than older drugs like imipramine, since they specifically acted on the serotonin transporter, and therefore didn’t have many of the side effects that were said to result from non-specific effects on many neurochemical systems, including dry mouth. Contrary to popular belief, however, the newer generations of antidepressants don’t work any better than the old ones, with the possible exception of the dual reuptake inhibitors.

The primary improvement of SSRIs over tricyclics is a questionable decrease in side effects, and the fact that you can’t kill yourself by taking an overdose of them. However, drop out rates are not a lot worse with the old drugs and the new drugs, suggesting that new side effects are just as bad as the old ones. In general the sexual dysfunction and jitteriness that come with the SSRIs can be just as bad as the sedation and dry mouth that come with the old ones. The conquering of the market by the SSRIs was mainly a triumph of marketing skills.

The SSRI medications have not been shown to work better than the older tricyclics. In fact, they actually have less efficacy than is commonly believed (DUAG 1990). The Danish Study Group found that the older tricyclic medication clomipramine worked better for severe depression than paroxetine, although it had more side effects. A review from 15 years ago showed that fluoxetine had only modest efficacy over placebo, with over 80% of the improvement accounted for by a placebo effect (Kirsch et al 2002).


A more recent meta analysis from data submitted to the FDA also showed that 80% of the improvement with antidepressants come from the placebo response. When the data of all studies performed on venlafaxine (Effexor), fluoxetine (Prozac), and nefazodone (Serzone), was lumped together, there was only about a 2-point improvement on a 62 item scale (the 21 item Hamilton Depression Scale) above and beyond the placebo response. The response to this was that the effects of antidepressants are modest, even if real, and that it is not ethical to give placebo.

It was also pointed out that the efficacy of SSRIs is greater than other areas of medicine, like the use of statins. Others have argued that SSRIs may not be much better than placebo, but that the relapse rate is much higher on placebo. However, studies following patients who were treated with antidepressants did not show that they did better over the long haul, in fact they may have done worse, even accounting for baseline differences in symptom severity (Moncrieff and Kirsch 2005). There are no studies showing that in the long run people treated with antidepressants are better off. It might be questioned whether a 2 point increase on a 62 item scale that may not be sustainable is a clinically meaningful improvement.

Worry over the efficacy of SSRIs prompted a re-examination of the efficacy of antidepressants in general, and a look at how placebos may work just as well. A meta-analysis showed that there was a highly variable response to placebos, up to 50%, and that the placebo response rate in studies of depression seemed to be growing over the years. In addition, studies in private research firms seemed to be having higher placebo response rates than in universities, suggesting differences in populations, assessments, or inducements for participation.

A more troubling problem is the potential for suicidality associated with SSRIs. The FDA recently added a warning that SSRI antidepressants may increase the risk of suicidal thoughts or suicide. Recent meta-analyses (see here and here) showed adults taking SSRIs showed no increase in suicidal thoughts or attempts, while there was a 57% increase in non fatal self harm with SSRIs that was of borderline statistical significance. Another meta-analysis did show a greater than two-fold increase in fatal and non-fatal suicide attempts in patients on SSRI versus placebo, and on SSRI compared to other non-medication treatments. The risk was 5.6 per 1000 patient years (the number of years people take the drug times the number of patients). In other words, if 100 people each took an SSRI for 10 years, about five of them would make a suicide attempt that they wouldn’t have done if they weren’t on suicide.

There was no difference, however, between SSRIs and the older tricyclic antidepressants, suggesting that all antidepressant medications may carry an increased risk of suicide. Questions about suicidal thinking with antidepressants have been around for years, and occurred with the tricyclics. Some doctors, including my father (who is a retired psychiatrist) offer the explanation that the increase in energy that antidepressants experience often gives the suicidal patient enough stamina to go through with the act. Another disturbing trend that came from this analysis was the change in suicidal thoughts over time. There are 24.5 million visits for depression in the US per year, a 70% increase from 15 years ago. Sixty nine percent of these visits result in a prescription for an antidepressant. The analysis showed that the risk of suicidal thinking and suicide itself has been gradually increasing over the years. It is unclear if this is fueled by an increase in prescribing, primarily by primary care physicians, or other causes.

The latest group of antidepressants has dual reuptake inhibition for serotonin and norepinephrine (SNRIs), and includes venlafaxine (Effexor) and duloxetine (Cymbalta). In general, effexor and duloxetine have shown better treatment response for depression than SSRIs and tricyclics. One study looked at data from a number of randomized, placebo controlled trials of Effexor, tricyclic antidepressants and SSRIs for the treatment of depression. Treatment response was defined as a 50% reduction in symptoms of depression. Forty-four studies with 4033 patients were included.

Overall, venlafaxine had a success rate of 74% that was statistically significantly better than SSRIs, which only had a 61% success rate, and tricyclics, which only had a 58% success rate. The difference in the efficacy of tricyclics and SSRIs was not statistically significant. However, it is worth noting that a larger number of patients dropped out of treatment while on tricyclics because of side effects. Other studies have shown better responses for venlafaxine and duloxetine than tricyclics and SSRIs. Venlafaxine has been associated with a dose dependent increase in blood pressure. Venlafaxine seems to carry the greatest risk of suicidality amongst all of the antidepressants, with a three fold increased risk of attempted or completed suicides.

See me talk about the drug industry and our film “The Goose That Laid the Golden Egg” at the link below and view our kickstarter campaign here.