The term "antidepressant" was new to the English language in the 1950s when it was coined by a researcher who was working on the use of certain drugs that were used to treat tuberculosis and which turned out to be MAOI drugs that were subsequently shown to have antidepressant properties. Subsequently, tricyclic antidepressants (named for their three cyclic ring chemical structure, TCA) came to the market, followed by the selective serotonin reuptake inhibitors (SSRI) whose initial U.S. entrant was fluoxetine (Prozac), which was introduced in 1986. These revolutionized the treatment of anxiety and depression. At about the same time, the norepinephrine dopamine reuptake inhibitor (NDRI) bupropion (Wellbutrin) was introduced and these were followed by the serotonin norepinephrine reuptake inhibitors (SNRI) venlafaxine, desvenlafaxine, duloxetine (Effexor, Pristiq, Cymbalta).
A Cochran Collaboration meta-analysis comparing SSRIs and other antidepressants did not demonstrate significant efficacy differential between SSRIs and TCAs but did demonstrate that SSRIs were discontinued at a lower rate due to safety and tolerability. Papakostas compared SSRIs to SNRIs and found the SNRIs to be slightly more efficacious with a response rate of 63% vs 59%. However, it appears that the SSRIs are more acceptable as measured by the number of drop-outs in the studies. However, using the discontinuation rate as a measure for tolerability and safety is somewhat problematic since the variety of side effects or adverse events can be very large. Additionally, not all studies agree that the SNRIs have superior efficacy. Furthermore, the drug trials have very few patients who are classified as mild to moderate depression. The robustness of response may be related to the baseline severity of the depression, which is what Fournier et.al found.
Patients with MDD are at higher risk for suicide during the course of treatment. Much of the data regarding risk of suicidality comes from industry-generated studies which routinely exclude high risk patients with suicidal ideation, substance abuse, and co-morbid personality disorders, which biases trials to detect emerging suicidal ideation and behavior and which makes the data difficult to generalize to real world psychiatric practice. Indeed, Mulder conducted a study which included patients with personality disorders. They found that only 3% had emergent suicidal ideation when those with suicidal ideation in the prior six months were excluded. Other investigators have found decreased rates of suicide when antidepressants were prescribed. Gibbons et.al. found an increase in suicide among adolescents after the US FDA and the European equivalent issued the warnings of an association between antidepressant use and suicide. Antidepressant prescriptions decreased by 20% after the warning. There is an important issue of bipolar depression in this age group which is beyond my discussion in this blog.
The delayed onset of clinical effect has occupied a canonical position in psychiatric therapeutics and the position has usually been taken that six to eight weeks of an adequate dose is required before concluding an agent is ineffective. In a meta-analysis conducted by Papakostas et al., sustained early response to antidepressants was more common than patients treated with placebo at weeks 1 and 2. The authors conclude that an antidepressant response can occur in the first two weeks of treatment. Indeed, I find that if a patient does not respond a little in the first two weeks, it is unlikely he/she will respond and I generally change agents. (Remember, it is always dosage and duration which allow a person to conclude whether an agent is ineffective or effective. Under-dosing and under-utilization is called pseudoresistance.) If there is a partial response at two weeks, I generally adjust the dose and/or augment. Emerging data suggest that early response is predictive of longer-term outcomes.
Major Depressive Disorder (MDD) is a highly recurrent disorder and has been studied by many researchers including Mueller, Keller Coryell, and Maj. The risk of recurrence rises with the each subsequent episode as well as the severity of the illness in the index episode. The presence of significant residual symptoms also is predictive of recurrences as well as reduced quality of life and impaired social/vocational functioning. All antidepressants have been studied in acute treatment as well as maintenance which suggests that those antidepressants effective in acute treatment will also be effective in maintenance treatment.
Since the response or remission rate for the first trial of antidepressant is less than 100% and also variable depending on the definition of the terms as well as the study examined, a strategy for augmentation was developed. The principal augmentation strategies for antidepressants include a second antidepressant, atypical antipsychotics, lithium, triiodothyronine (T3), SAMe, n-acetyl-cycteine (NAC), pramipexole, modafinil, and amphetamines/methyphenidate.