The Risk-Benefit Ratio Encourages the Use of Antidepressants in Unipolar Depression
Wednesday we reviewed new data that shows that despite the FDA warning that antidepressants can increase suicidal ideation among young people in the first few months they are taken, antidepressants actually reduce acute suicidal ideation and decrease suicidal acts. As we described last year in our article on five myths about antidepressants, antidepressant treatment in recurrent unipolar depression is important to patients’ long-term wellbeing, cognitive functioning, and even life expectancy.
Untreated depression, and particularly untreated recurrent depression, carries high risks not only for lethality by suicide, but also for increases in medical mortality, particularly from cardiovascular disease. In addition to these medical risks, data from many studies suggest that a higher number of prior depressions is associated with increased cognitive dysfunction, and recent large data sets from a case registry in Denmark indicate that patients with four or more prior unipolar or bipolar depressive episodes have double the risk of receiving a diagnosis of dementia in old age. Thus, depressions are dangerous for a patient’s psychological, medical, and cognitive health.
Antidepressants Are Highly Effective in Depression Prevention
In 1992 researcher John Davis completed a meta-analysis of all antidepressant data available at the time in unipolar depression studies and not only found that antidepressant continuation was more effective than placebo in reducing the likelihood of later depressions, but also calculated that the statistical likelihood that this finding was due to chance was minuscule, i.e., p<10-34. John Geddes and colleagues in a meta-analysis in 2003 indicated that there was an approximate 70% reduction in the risk of depressive recurrences with antidepressant continuation compared with discontinuation.
Treatment of a first or second episode of unipolar depression is recommended for six to nine months following achievement of remission. After a third episode, all treatment guidelines of which this editor is aware recommend long-term preventive treatment with antidepressants, particularly if episodes have been severe or close together temporally. This long-term antidepressant continuation for prophylaxis is much like long-term treatment of high blood pressure or high cholesterol recommended for those with or at high risk for cardiovascular disease.
There is some evidence that cognitive behavior therapy reduces the risk for depressive recurrence in those discontinuing antidepressant treatment, but it appears maximally beneficial to engage both psychotherapeutic and pharmacological treatment to prevent future episodes.
In most longitudinal studies, about 20-25% of patients who remain on antidepressants for several years still relapse. However, this is considerably less than the more than 50% who relapse within the first year after discontinuing an antidepressant that had been acutely effective. The rate of relapse following antidepressant discontinuation increases to about 85% by the third year off treatment in those with prior recurrent depressive episodes.
In addition to preventing relapse, antidepressants may also have positive effects on the brain. They increase brain-derived neurotrophic factor (BDNF), a protective factor important for long-term learning and memory that decreases when stressors and episodes of depression occur. In addition to these increases, Yvette Sheline has demonstrated that patients with unipolar depression who were on antidepressants more of the time experienced less hippocampal atrophy with aging compared with those treated with antidepressants less of the time.
It is important to put the risk/benefit ratio of antidepressant treatment for unipolar depression in perspective, particularly since some articles in the mainstream press, including one on the cover of Newsweek last year, suggest that acute treatment with antidepressants may not be much more effective than placebo. Antidepressants sometimes fail to show efficacy acutely compared with placebo, but this is not unexpected given the relapsing and remitting nature of the illness and difficulties of research design. While some of these articles are narrowly factual about the small magnitude of acute antidepressant efficacy compared to that of placebo, they fail to communicate the breadth of data noted above about the large effects of antidepressants in prevention.
In blind studies, when patients improve on antidepressants and then are randomized to either a group that continues preventive antidepressants or a group in which the antidepressant treatment is replaced by a placebo, the group that continues antidepressant treatment is more successful in avoiding future episodes at a level that is statistically astronomical. Since greater numbers of depressions are associated with increased dysfunction, disability, cognitive dysfunction, suicide risk, and premature loss of life from excess medical mortality, antidepressants are extremely important in helping prevent these risks.
Limited Risks of Long-Term Antidepressants
There are some real risks associated with antidepressants in addition to the FDA warning about suicidal ideation. Some are medical risks and some relate to the fact that antidepressants are not equally effective in all patients.
Medical risks that come with antidepressant treatment include 20% increased risk of cataracts, but this readily correctable medical problem pales in comparison to the enormous risks associated with depression recurrences. There is some evidence of more serious medical risks. Recent studies have suggested that antidepressants are associated with cardiovascular problems and cancer. However, these studies do not always control for the fact that depression itself increases the risks of these medical illnesses, and those with more severe depression are more often treated with antidepressants.
Antidepressants may not be effective in some individuals. Antidepressants can lose their effectiveness over time or fail to adequately prevent recurrence, and other strategies may be needed. One or more antidepressant augmentation strategies may be necessary to achieve a full remission from depression. As discussed in previous BNNs, these could include folate, lithium, T3, N-acetylcysteine, and many others.
Antidepressants Not Recommended for Bipolar Depression
Antidepressants are not usually effective in bipolar depression. A recent meta-analysis published by Sidor and MacQueen in the Journal of Clinical Psychiatry in 2011 indicates that antidepressants, even when used as augmentation to mood stabilizers, are not more effective than placebo as acute treatments for bipolar depression. They may even increase the switch rate of cycling into the next episode of mania or depression in some individuals. This occurs particularly in those with more rapid cycling presentations (i.e., those with four or more episodes of bipolar depression or mania per year).
Recent data by Ghaemi showed that antidepressant continuation in bipolar depressed patients who had a period of remission of several months was associated with a lower and delayed recurrence of the next depressive episode, but in those with a prior history of rapid cycling, antidepressant continuation was associated with an increased frequency and rapidity of recurrent depressive episodes. A few studies suggest that antidepressants can be effective in patients with bipolar II depression who have isolated, intermittent episodes and are not highly recurrent.
Thus, the endorsement of antidepressant prophylaxis applies only to those with unipolar recurrent depressions. For those with bipolar depression an entirely different set of treatment approaches and guidelines must be considered.
Benefit-to-Risk Ratio Positive for Antidepressants in Unipolar Depression
Since recent findings show that antidepressants do not cause suicide, but actually prevent it, the benefit-to-risk ratio for long-term antidepressant prophylaxis (instead of antidepressant discontinuation) is enormously positive. The benefits are huge and important and the risks are relatively small. Patients need this full picture about antidepressant efficacy so that they can make informed decisions about long-term prevention of recurrent unipolar depressions.