A large study of women who took selective serotonin reuptake inhibitor (SSRI) antidepressants in the month before pregnancy and throughout the first trimester suggests that there is a smaller risk of birth defects associated with SSRI use than previously thought, though some risks were elevated in women who took paroxetine or fluoxetine.
The 2015 study, by Jennita Reefhuis and colleagues in the journal BMJ, investigated the drugs citalopram, escitalopram, fluoxetine, paroxetine, and sertraline, and examined birth defects that had previously been associated with SSRI use in smaller studies. The participants were 17,952 mothers of infants with birth defects and 9,857 mothers of infants without birth defects who had delivered between 1997 and 2009.
Sertraline was the most commonly used SSRI among the women in the study. None of the birth defects included in the study were associated with sertraline use early in pregnancy. The study found that some birth defects were 2 to 3.5 times more likely to occur in women who had taken fluoxetine or paroxetine early in their pregnancies.
Five different birth defects, while uncommon, were statistically linked to paroxetine use: anencephaly (undersized brain), heart problems including atrial septal defects and right ventricular outflow tract obstruction defects, and defects in the abdominal wall including gastroschisis and omphalocele. Two types of birth defects were associated with fluoxetine use: right ventricular outflow tract obstruction defects and craniosynostosis (premature fusion of the skull bones). Absolute incidence of these defects was also low.
One-third of people who have strokes face depression afterward. New research is looking to expand the safe options for the treatment of depression following strokes. At the 2015 meeting of the Society of Biological Psychiatry, researchers led by Leandro Valiengo presented their successful randomized, sham-controlled double-blind study of transcranial direct current stimulation for post-stroke depression. Forty-eight people who had depression following a stroke were randomized to receive either a sham procedure or tDCS in twelve 30-minute sessions over a period of six weeks. After the six weeks, those who received tDCS had fewer symptoms of depression, more remission, and better response. There were no serious side effects.
TDCS is very low-level electrical current that has a positive (anode) or negative (cathode) electrode. Anodal stimulation of the cortex is usually associated with positive effects on mood and cognition. TDCS sessions in this study consisted of 2-mA anodal left/cathodal right dorsolateral prefrontal stimulation.
Editor’s Note: Placebo-controlled studies have repeatedly indicated that patients who have a stroke show better neurological and psychiatric response afterward when they are given an selective serotonin reuptake inhibitor (SSRI) antidepressant, whether or not they have depression or a prior history of depression. If a neurologist does not suggest treatment with an SSRI after a stroke, ask why not. Since antidepressants increase brain levels of brain-derived neurotrophic factor (BDNF) and increase neurogenesis, they could help with post-stroke recovery.
In the past there has been some concern that selective serotonin reuptake inhibitor (SSRI) antidepressants taken during pregnancy could increase an infant’s risk of cardiac problems. There was particular concern that the SSRI paroxetine could lead to right ventricular outflow tract obstruction, and sertraline could lead to ventricular septal defects. A 2014 study by KF Huybrechts et al. in the New England Journal of Medicine analyzed data from 949,504 women in a Medicaid system from three months before pregnancy until one month after delivery during the years 2000-2007.
Infants born to mothers who had taken antidepressants during their first trimester were compared to infants whose mothers had not taken antidepressants. In total, 6.8% or 64,389 women had used antidepressants in their first trimester.
While the rate of cardiac defects in newborns was greater among those mothers who had taken antidepressants (90.1 infants per 10,000 infants who had been exposed to antidepressants versus 72.3 infants per 10,000 infants who had not been exposed to antidepressants), this relationship diminished as confounding variables were removed. The relative risk of any cardiac defect after taking SSRIs was 1.25, but this decreased to 1.12 when restricted to only those mothers who were diagnosed with depression, and to 1.06 when the researchers controlled for things like depression severity. (All relative risk numbers were calculated with a 95% confidence interval.)
The researchers concluded that there is no substantial risk of increased cardiac defects in children born to mothers who took antidepressants during their first trimester.
Many patients with depression require two or more treatments in order to achieve remission. In a 2011 study by Trivedi et al. published in the Journal of Clinical Psychiatry, patients with major depressive disorder who had not responded adequately to selective serotonin reuptake inhibitor (SSRI) antidepressants improved when an exercise regimen was added to their regular treatment.
The patients, aged 18-70 years old, were all sedentary at the start of the trial. They were randomized to one of two exercise regimens: a high dose regimen (16 kcal/kg per week, equivalent to walking at about 4 mph for 210 minutes per week) or the low dose (4 kcal/kg per week, equivalent to walking at 3 mph for about 75 minutes per week). Both groups improved significantly by the end of the study. Remission rates (adjusted for differences between groups) were 28.3% for the high dose group and 15.5% for the low dose group.
The rates of improvement with exercise were similar or better to those commonly seen with other augmenting agents such as lithium, T3, buspirone, and atypical antipsychotics, but without side effects and other inconveniences such as blood monitoring.
Other studies have indicated that exercise by itself and in combination with other treatments has efficacy in depression. Exercise can change serotonin and norepinephrine function and can increase brain-derived neurotrophic factor (BDNF), a, and neurogenesis in the hippocampus.
The researchers looked for moderating variables that may have affected the outcomes of various participants. Men, regardless of family history of mental illness, had better remission rates in the high dose group. Women without a family history of mental illness also improved more in the high dose group, while women with a family history of mental illness improved more in the low dose group, though this finding was statistically nonsignificant.
While the researchers observed that those in the high-dose group did exercise more than those in the low-dose group, participants in the high-dose group had more difficulty sticking to their exercise regimen. It may be that even though high doses of exercise offer slightly higher rates of remission, lower doses may be more effective clinically if patients can stick to the low-dose regimen better.
Research has shown that serotonin-selective reuptake inhibitor (SSRI) antidepressants can be useful for severe premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). According to a 2006 article by Steiner et al. in the Journal of Women’s Health, there are various ways that SSRIs can be used to treat PMS symptoms such as irritability, depressed mood, dysphoria, bloating, breast tenderness, appetite changes, and psychosocial function, including intermittent dosing just in the two weeks prior to PMS. Usually doses for PMS are lower than those used to treat depression.
For those with mood symptoms that continue throughout the month, continuous (daily) dosing may improve PMS symptoms. For those whose mood symptoms worsen during PMS, continuous dosing can be intermittently increased from around the time of ovulation to a few days after the period begins. For those women with mood symptoms only during PMS, intermittent dosing only during those weeks between ovulation and the period seems to be helpful and minimizes side effects of the SSRIs.
Editor’s Note: While SSRIs sometimes take weeks to reach maximum benefit for those with depression, intermittent dosing for women with severe PMS seems to be helpful. This may be because SSRIs acutely increase the neurosteroid allopregnanolone, which enhances GABA-A receptor activity, associated with improvement in mood and anxiety.
Much has been written about the use of selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy. In a review of 920,620 births in Denmark (1995 to 2008) that Jimenez-Solem published this year in the American Journal of Psychiatry, no link was found between any of the SSRIs used in any trimester and risk of stillbirth or neonatal mortality. The only exception was a possible association of three-trimester exposure to citalopram and neonatal mortality.
Editor’s Note: These new data may be of importance to women considering antidepressant continuation during pregnancy when there is a high risk for a depressive relapse. A maternal depressive episode (like other stressors such as anxiety or experiencing an earthquake) during pregnancy does convey adverse effects to the child, so appropriate evaluation of the risk/benefit ratio or staying on an antidepressant through a pregnancy is important.
In 2004, the Federal Drug Administration issued a “black box warning” about increased risk of suicidal thoughts and behavior in children and adolescents taking selective serotonin reuptake inhibitors (SSRIs). See here for an overview from the National Institute of Mental Health.
An article published in the Archives of General Psychiatry earlier this year analyzed data from studies of fluoxetine and venlafaxine in youth, adults, and geriatric patients to determine if antidepressant use is linked to suicide. The drugs decreased both depressive symptoms and suicidal thoughts and behavior in adults and the geriatric population. They seemed to have no effect on suicidal thoughts or behavior in the youth.
For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication.
Researchers have long suspected a link between the use of selective serotonin reuptake inhibitors, or S.S.R.I.’s, and [pulmonary hypertension in babies], but previous studies have been small and inconclusive (with results ranging from there being no link to a six times greater risk).
This research, based on 1.6 million births in Denmark, Finland, Iceland, Norway or Sweden from 1996 to 2007, showed that among women using S.S.R.I.’s, the risk of persistent pulmonary hypertension for infants more than doubled (particularly for use late in pregnancy). It’s still a small risk: 3 in 1000 births, as opposed to 1.2 per 1000 births overall. But it’s a small risk of a serious problem.
Pulmonary hypertension, Dr. Juliette Madan, a pediatrician at the Dartmouth Hitchcock Medical Center explained, is diagnosed when an infant struggles to get enough oxygen into her lungs, and therefore into her bloodstream. The condition can be deadly, although Dr. Madan said that it’s usually treatable — with possible lifelong consequences.
But other research suggests that untreated depression during pregnancy has its own risks, including pre-term birth and low birth weight. Given that, how should a pregnant woman and her doctor weigh the competing risks?
See the New York Times for a discussion on how to balance mother’s health with babies’ health.
Tracy L. Greer of the University of Texas Southwestern in Dallas presented an abstract at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 that suggested that exercise improved the cognitive function of patients being treated with selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder.
Thirty-nine participants reported cognitive impairment at baseline. Subjects were randomized to receive antidepressant treatment in the form of an SSRI augmented by either an exercise regimen designed to burn 16 kilocalorie/kg per week (kkw) or one designed to burn 4 kkw. Both exercise regimens resulted in improved response time on a measure of attention, and for the higher intensity (16 kkw) exercise group, there were improvements in response time for visual memory tasks as well as decreased errors on an executive function task.
Editor’s note: There is a somewhat mixed literature on the efficacy of exercise in potentiating antidepressant effects of other treatments. Recent data by Fred Gage and colleagues showed that in animals, exercise increased not only brain-derived neurotrophic factor (BDNF), which seems to be necessary for long-term learning and memory, but also the formation of new neurons (neurogenesis). Gage found that new neurons that migrated to the dentate gyrus of the hippocampus were more excitable than older neurons and were important in a variety of cognitive tasks.
The newer neurons could more precisely distinguish between different stimuli, while the older neurons were sufficient only for discriminating stimuli that were widely and obviously different from each other.
Thus, the increase in new neurons and BDNF that may follow exercise and antidepressant use may be associated with some cognitive improvement in depression, particularly in the realm of response speed and perhaps also in making relatively fine discriminations among relatively similar objects.
While not much evidence for the effect of exercise on cognition has been collected in humans, exercise has many other benefits. Since it is good for cardiovascular fitness and wellbeing, as well as potentially generating new neurons that could play an important role in fine cognitive discriminations, encouraging exercise in depressed patients (especially as their depression improves and they have renewed motivation to engage in exercise regimens) could be of value, even if exercise is not a guaranteed enhancer of antidepressant effects per se.
The B vitamin folate has been shown to be a useful augmentation treatment for patients who are nonresponsive or only partially responsive to selective serotonin reuptake inhibitor (SSRI) antidepressants. Treatment with folate works even in those who are not folate-deficient at baseline.
When folate is broken down in the body by reductase enzymes, it turns into the active form L-methylfolate, and crosses the blood-brain barrier. Maurizio Fava and colleagues at Massachusetts General Hospital (MGH) performed two placebo-controlled, randomized studies of L-methylfolate for depression. There was significantly greater improvement when SSRIs were augmented with L-methylfolate than when they were augmented with placebo. The results were significant with the use of 15mg of L-methylfolate, but not with 7.5mg, suggesting dose-related effects. Read more