Syndromes and Trials
Discontinuation syndrome
Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment. It is generally believed that the side effects of the fluoxetine discontinuation are mild, and one of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent, in cases where tapering off the dose of the original SSRI is ineffective. The double-blind controlled studies support this opinion. No increase in side effects was observed in several studies when the treatment with fluoxetine was blindly interrupted for a short time (4–8 days) and then re-instated, this result being consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline (Zoloft) in these studies, and significantly more during the interruption of paroxetine. In a longer, 6 week-long, blind discontinuation study, an insignificantly higher (32% vs 27%) overall rate of new or worsened side effects was observed in the group that discontinued fluoxetine than in the group that continued treatment. However, a significantly higher 4.2% rate of somnolence at week 2 and 5-7% rate of dizziness at weeks 4-6 were reported by the patients in the discontinuation group. This prolonged course of the discontinuation symptoms, with dizziness persisting to the end of the study, is also consistent with the long half-life of fluoxetine in the body.
Suicidality in antidepressant trials
The FDA requires all antidepressants, including fluoxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was criticized by Donald Klein who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for completed suicide, and it is still possible that antidepressants may prevent actual suicide while increasing suicidality. This opinion goes against the general consensus that "suicidal ideation has been associated with suicide attempt in retrospective studies and with suicide in prospective studies."
Suicidality and fluoxetine
Suicidal ideation and behavior in clinical trials are rare. For the above analysis the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50% (not statistically significant due to the low number of cases), and in adults decreased the odds of suicidality by approximately 30% (statistically significant). Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.
***