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. Read more
Why Preventive Treatment Is Important
RTMS Versus ECT
We’ve been posting about repeated transcranial magnetic stimulation (rTMS), a treatment in which a magnetic field is applied to a patient’s head, where it is able to affect tissue 2-3 centimeters into the brain.
In randomized, controlled, head to head comparisons of electroconvulsive therapy (ECT) and repeated transcranial magnetic stimulation (rTMS), ECT often proves superior, particularly for a more severe psychotic or medically compromised patient. Nonetheless, for a more routine patient with non-psychotic depression, multiple studies have shown approximate equivalence of rTMS and ECT, while rTMS may have a superior benefit-to-risk ratio because it brings less risk of cognitive dysfunction. Thus, given almost equivalent efficacy for some subgroups of depressed patients, and a clear advantage for rTMS in terms of lack of cognitive side effects, this editor/clinician would recommend a course of rTMS prior to a series of ECT for the subgroup of non-emergency treatment-resistant depressed patients.
However, for highly treatment-refractory, severe, and particularly psychotic depression, few treatments appear to approach the efficacy and rapid response onset of electroconvulsive therapy (ECT). ECT as given in the modern era involves anesthesia and muscle paralysis while the patient is mechanically ventilated in order to prevent any damage from muscle contractions during the seizure. Read more
Long-Term Treatment with Lithium, Valproate, or Carbamazepine: Lithium Best for Most Patients
Shannon Stepan, Eric Peselow and Nunzio Pomara from Maimonides Medical Center in Brooklyn, NY, have analyzed naturalistic observations of long-term maintenance treatment of bipolar disorder with valproic acid, lithium, and carbamazepine and found that patients on lithium went much longer before experiencing an episode of mania or depression than patients taking carbamazepine or valproate.
The team followed 225 outpatients for up to 124 months, or until they had a manic or depressive episode or dropped out of the study during a well phase. Ninety-eight patients took lithium, 78 took valproate, and 50 took carbamazepine. Fifty-two percent of the participants dropped out of the study during a well phase.
One hundred three patients (45.8%) had either a manic or depressive episode during the study. This included 36.7% of the patients taking lithium, 55% of patients taking valproate, and 50% of patients taking carbamazepine. Median time until a first episode was 45 months for the entire sample, 36 months for those patients on valproate, 42 months for those on carbamazepine, and 81 months for those on lithium. A statistical analysis known as a Cox regression model indicated that patients taking valproate had a significantly higher risk of having a manic or depressive episode than those taking lithium.
Editor’s note: These naturalistic data are highly consistent with a number of more controlled clinical studies. In particular, the BALANCE study by Geddes et al. (2010) reported that lithium was superior to valproate on most outcome measures in a two-year randomized study, and that the combination of lithium and valproate was significantly better than valproate alone. Read more
Inflammation and Oxidative Stress in Bipolar Disorder
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders conference in Sao Paulo, Brazil in March reported new data relevant to inflammation and oxidative stress. Both inflammation and oxidative stress increase risk of cardiovascular disorders, and patients with inadequately treated mood disorders lose 10 or more years of life expectancy from cardiovascular disorders compared to the general population. Inflammation and oxidative stress may also contribute to the symptoms, evolution, and progression of the mood disorders themselves.
It is possible that these two processes could become new targets for therapeutic intervention in addition to more traditional psychopharmacological drugs that primarily target the neurotransmitters dopamine, norepinephrine, serotonin, and the neurotrophic factor BDNF. Read more
