Neonatal outcomes after prenatal exposure to SSRIs and maternal depression

 Duloxetine for the Treatment of Major Depressive Disorder: A Closer Look at Efficacy and Safety Data Across the Approved Dose Range

High risks of using valproate in early pregnancy – more evidence  

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Neonatal outcomes after prenatal exposure to SSRIs and maternal depression

Source: Arch Gen Psychiatry 2006;63:898-906.

 The authors of this study note how it is hard to distinguish the effects of neonatal exposure to selective serotonin reuptake inhibitors (SSRI) from the effects of the disease itself (i.e. maternal depression) on neonatal health. They sought to determine whether the effect of exposure to SSRIs and depression on neonatal health differs from that of exposure to maternal depression alone.

They studied data from mothers and their infants born during a 39-month period (n=119,547) in British Columbia, Canada. Population health data and records of neonatal birth outcomes were linked to records of maternal health and prenatal maternal prescriptions for SSRIs.

The researchers compared the outcomes of infants of depressed mothers treated with SSRIs (SE-D) with outcomes from infants of depressed mothers not treated with medication (DE) and non-exposed controls. To account for differences in maternal characteristics that may have led to SSRI use during pregnancy (ie, illness severity), propensity score matching was used to identify a subgroup of mothers in the DE group who were similar to the mothers in the SE-D group.

The main results presented are as follows:

• The birth weight of SE-D infants was significantly lower than DE infants (by -32g; 95% CI -1 to -64g, p=0.05), although differences in the incidence of birth weight less than the 10th percentile for gestational age were not significant.

• The gestational age for SE-D infants were significantly less than for DE infants (by -0.35 weeks; -0.25 to -0.45, p<0.001)

• The proportion of infants born at less than 37 weeks was significantly higher in the SE-D group (0.02; –0.009 to –0.04, respectively)

• An increased proportion of SE-D infants had neonatal respiratory distress (13.9% vs 7.8%), jaundice (9.4% vs 7.5%), and feeding problems (3.9% vs 2.4%) compared with DE infants (95% CI of difference, 0.042-0.079, 0.003-0.334, and 0.005-0.025, respectively).

• When outcomes were compared between the SE-D group and the DE subgroup with propensity score matching, only the incidence of birth weight less than the 10th percentile and respiratory distress were significantly different between the groups.

The authors conclude that prenatal SE-D exposure was associated with an increased risk of low birth weight and respiratory distress, even when maternal illness severity was accounted for. They comment that these findings are contrary to the expectation that treating depressed mothers with SSRIs during pregnancy would be associated with lessening of the adverse neonatal consequences associated with maternal depression.

They provide two possible reasons for these findings. Firstly, neonates born to mothers who were treated with SSRIs may have had adverse outcomes because their mothers had more severe depression (bias due to illness severity). If the SSRIs lessened the effect of maternal depression, then in the absence of treatment with an SSRI, outcomes for these infants may have been even worse. Alternatively, SSRIs could have affected outcomes separate from the effect of depression.

They do however emphasise that ‘none of these findings should diminish the clinical urgency of recognising and treating maternal depression during pregnancy by using a variety of available pharmacological and nonpharmacological strategies. At present, the need to use antidepressants must be weighed against the risks of untreated or undertreated disease, and the decision should made by an informed patient with her physician on a case-by-case basis’.

Link: http://archpsyc.ama-assn.org/cgi/content/abstract/63/8/898

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Duloxetine for the Treatment of Major Depressive Disorder: A Closer Look at Efficacy and Safety Data Across the Approved Dose Range

Source: J Psychiatr Res. 2006;40:337-348

OBJECTIVE: This analysis focuses on efficacy and safety data obtained from studies of duloxetine for the treatment of major depressive disorder (MDD) within the approved dose range of 40-60 mg/day. METHOD: Efficacy and safety data were obtained from the acute phase portions of four randomized, double-blind, placebo-controlled clinical trials in patients meeting DSM-IV criteria for MDD. In Studies 1 and 2, patients were randomized to duloxetine 60 mg once daily (QD) (n=123 [Study 1]; n=128 [Study 2]) or placebo (n=122 [Study 1]; n=139 [Study 2]) for 9 weeks. In Studies 3 and 4, patients were randomized to duloxetine 20 mg twice daily (BID) (n=91 [Study 3]; n=86 [Study 4]) or placebo (n=90 [Study 3]; n=89 [Study 4]) for 8 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score (primary outcome), HAMD17 subscales, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. Safety assessments included rates of discontinuation due to adverse events, spontaneously reported treatment-emergent adverse events, and changes in vital signs. RESULTS: In both studies of duloxetine 60 mg QD, mean change in HAMD17 total score was significantly greater in duloxetine-treated patients compared with placebo (Study 1, p<.001; Study 2, p=.024). At a dose of 20 mg BID, duloxetine demonstrated significant superiority over placebo on the HAMD17 total score in one of the two studies (Study 4, p=.034). Probabilities of remission among patients receiving duloxetine 60 mg QD were 44.2% in Study 1 (p<.001 vs. placebo) and 43.0% in Study 2 (NS), while for patients receiving duloxetine 20 mg BID the probabilities of remission were 27.2% in Study 3 (NS) and 36.1% in Study 4 (NS). Across the six assessed VAS measures of pain severity and interference, the main effect of treatment for duloxetine 60 mg QD was significantly superior to placebo on 7 of the 12 outcomes in Studies 1 and 2, while duloxetine 20 mg BID was not superior to placebo on any of the 12 outcomes in Studies 3 and 4. The rate of discontinuation due to adverse events was 13.1% among patients receiving duloxetine 60 mg QD, and 11.9% at a dose of 20 mg BID. The most frequently reported treatment-emergent adverse events at both doses included nausea, headache, dry mouth, dizziness, and insomnia. The incidence of treatment-emergent nausea among patients receiving duloxetine 60 mg QD was 37.8%, compared with 16.4% among patients receiving 20 mg BID. CONCLUSION: Duloxetine provides safe and effective acute phase treatment of MDD at doses of 40-60 mg/day. Compared with placebo, the 60 mg QD dose was more consistently effective than the 20 mg BID dose. However, the incidence of certain treatment-emergent adverse events is likely to be lower at the 40 mg dose.

Link: http://www.medscape.com/medline/abstract/16271726 

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High risks of using valproate in early pregnancy – more evidence

Source: Neurology. 8 August 2006;67:407-412.

In utero exposure to the antiepileptic drug (AED) valproate poses a much higher risk of foetal death and serious birth defects than the 3 other most commonly used AEDs, a new study has found.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was originally designed to assess whether monotherapy with valproate, carbamazepine, lamotrigine, or phenytoin was associated with long-term cognitive and behavioural neurodevelopmental effects. However, as foetal outcomes were tracked, a high rate of serious adverse events, including major congenital abnormalities and foetal death associated with in utero exposure to valproate was detected, although the study was not designed to look for these outcomes. The NEAD study is an ongoing prospective observational study that includes 25 epilepsy centers in the United States and the United Kingdom. From October 1999 to February 2004, pregnant women with epilepsy who were on monotherapy with 1 of the 4 agents were enrolled. A total of 323 women and 333 children were included in the final analysis of the current report, of whom 110 were taking carbamazepine, 98 lamotrigine, 56 phenytoin and 69 valproate.

It was found that valproate appeared to produce an incidence of congenital malformations of over 17.4%, compared to carbamazepine 4.5%, lamotrigine 1.0% and phenytoin 7.1%. The incidence of foetal death was not higher with valproate (2.9%) compared to carbamazepine (3.6%), lamotrigine (0%) and phenyotin (3.6%). The authors conclude that these results combined with several recent studies provide strong evidence that valproate poses the highest risk to the foetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Link: http://www.neurology.org/cgi/content/abstract/67/3/407

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