Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review

OBJECTIVE: To review studies conducted to establish the risk of major congenital malformations in women exposed to serotonin reuptake inhibitors (SRIs) during the first trimester of pregnancy. METHODS: A literature search [corrected] was conducted within PsycINFO [corrected] EMBASE, MEDLINE and Cochrane databases from 1966 to October 2006, to identify studies assessing the risk of major malformations in infants whose mother was taking SRIs (SSRIs and SNRIs) during the first trimester of pregnancy. RESULTS: Fifteen studies were selected for the analysis: seven adopted a prospective cohort design and seven a retrospective design, of these one was a case-control study. DATA SYNTHESIS AND CONCLUSIONS: The reviewed studies suggest that exposure to fluoxetine, sertraline, citalopram and venlafaxine in early pregnancy is not associated with an increased risk of major congenital malformations. For paroxetine, recent data call for caution in prescribing such a drug in early pregnancy. For the other SRIs, the risk remains substantially undetermined, as data are so far scanty. Given this background, large prospective cohort studies are urgently needed to better assess the risk/benefit ratio of SRIs-treatment during pregnancy.     

Discontinuation rates for selective serotonin reuptake inhibitors and other second-generation antidepressants in outpatients with major depressive disorder: a systematic review and meta-analysis

The present study aimed to systematically compare overall loss to follow-up, discontinuation rates because of adverse events and discontinuation rates because of a lack of efficacy in published studies assessing the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) compared to other second-generation antidepressants in treating outpatients with major depressive disorder (MDD). We searched MEDLINE, Embase, The Cochrane Library, PsychLit and the International Pharmaceutical Abstracts from 1980 to 2004 (April). Twenty double-blinded, randomized controlled trials met our eligibility criteria and compared SSRIs to other second-generation antidepressants in adult outpatients with MDD. Pooled relative risks of discontinuation rates because of (i) any reason (overall loss to follow-up), (ii) adverse events and (iii) a lack of efficacy did not differ substantially between SSRIs as a class and other second-generation antidepressants. Taking the similar efficacy of second-generation antidepressant into account, our findings suggest that clinicians can focus on other practically or clinically relevant considerations such as costs, differences in side-effect profiles, onset of action or aspects of health-related quality of life to tailor a treatment to an individual patient's needs.     

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy

Anxiety disorders are common psychiatric conditions that typically require long‐term treatment. This review summarizes current knowledge of the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specific emphasis on the findings of recent randomized clinical trials and relevant neurobiological investigations. It is now well established that gabaergic, noradrenergic and serotonergic systems play a critical role in the pathophysiology of anxiety disorders, abnormalities in these systems being related to structural and functional alterations in specific brain areas such as the amygdala, prefrontal cortex, locus coeruleus and hippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and have shown to be efficacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages over selective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent first‐line pharmacological treatments in patients with anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partial response to standard treatments, and the increasing use of SNRIs reflects currently unmet clinical need, in terms of overall response, remission rates and treatment tolerability. Copyright © 2009 John Wiley & Sons, Ltd.     

Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review

Adding pindolol to serotonergic antidepressant treatment offers a potential strategy for producing a more rapid onset of action and an enhanced antidepressant effect. This review investigated whether pindolol enhances the efficacy of serotonergic antidepressant treatment in adult patients with depressive disorders at sequential time points up to 6 weeks. Search strategy: Cochrane Collaboration Depression, Anxiety and Neurosis-Controlled Trials Register plus unpublished trial data. Study selection: Randomised trials including depressed patients, comparing serotonergic antidepressants + pindolol with serotonergic antidepressants + placebo and using depressive symptom clinical outcomes scales. Data extraction: Clinical response at time points up to 6 weeks as defined by >50% depression scale score reduction was extracted for each trial as possible. Eleven studies were identified including unpublished data. The pooled odds ratios for dichotomous response to treatment at time points from 1 to 6 weeks were 2.39 (95% CI 1.40-4.06), 2.39 (1.74-3.29), 1.94 (1.46-2.58), 1.59 (1.16-2.18), 1.42 (0.87-2.31) and 1.28 (0.91-1.81). Time-to-event analysis showed a greater response with pindolol augmentation versus placebo (P = 0.04). There was significant heterogeneity between studies at some time points. Dropout rates did not significantly differ between treatment arms. This review suggests an overall beneficial clinical effect of pindolol augmentation, most clearly up to 4 weeks of treatment.     

Serotonin reuptake inhibitor antidepressants and pregnancy: many unanswered questions

(1) Serotonin reuptake inhibitor antidepressants are not teratogenic in animals. (2) Human data are limited, and most involve fluoxetine. (3) No data pointing to a teratogenic effect after fluoxetine exposure during the first trimester have been reported. (4) Self-resolving neurological signs have been observed in newborns exposed to fluoxetine at the end of pregnancy. (5) The paucity of data requires all prescribers of antidepressants to pregnant women to report any adverse events occurring in a child or mother to a teratogenicity or pharmacovigilance centre.     

Serotonin and noradrenaline reuptake inhibitors in animal models of pain

Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline and serotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathic pain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone.     

A review of the safety of selective serotonin reuptake inhibitors during pregnancy

Antidepressant treatment may be desirable or necessary during pregnancy; however, the benefit of treatment must balance the benefits to the mother with any risk to the developing fetus. In order to make educated, patient‐specific, benefit‐to‐risk assessments, an understanding of possible risks associated with in‐utero antidepressant exposure is important. We reviewed all published cohort‐controlled studies (n=4) and prospective surveys (n=5) regarding SSRI use in pregnancy. Outcomes from over 1000 fluoxetine‐exposed pregnancies, more than for any other antidepressant, indicate that first trimester fluoxetine exposure does not statistically significantly increase risk for spontaneous abortion or major malformation. Outcomes from nearly 300 pregnancies exposed to another SSRI (sertraline, paroxetine, or fluvoxamine) suggest the same conclusion. Following in‐utero SSRI exposure, birthweight, rates of prematurity, and postnatal complications appear similar to control values. Preschool age children exposed to fluoxetine in‐utero show no significant differences from controls in global IQ, language, or behavior; such long‐term data are not available for other SSRIs. The substantial clinical experience with fluoxetine‐exposed pregnancies and the preliminary data regarding other SSRIs is reassuring when considering depression treatment for women of child‐bearing potential. Copyright © 1999 John Wiley & Sons, Ltd.     

The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects

Mood and anxiety disorders are common in women during their childbearing years. The prevalence of depression has been reported to be between 10% and 16% during pregnancy. The use of selective serotonin reuptake inhibitors during pregnancy or lactation is, to date, not promoted because of lack of safety documentation. However, the off-label use of these drugs has been common for several years. In the treatment of mood and anxiety disorders during pregnancy, the serotonin reuptake inhibitors are often preferred over tricyclic antidepressants because of their relatively few adverse effects and safety in overdose. This has created concern among women planning pregnancies and pregnant women, as well as among their families and physicians. Several studies and reports of the use of serotonin reuptake inhibitors during both pregnancy and lactation have been published and advanced our knowledge. We here review and discuss those studies which have been published so far on this subject.     

Misoprostol and pregnancy: risk of malformations

(1) Misoprostol, a synthetic prostaglandin E1 analogue, is used to treat gastric and duodenal ulcers, and, in combination with mifepristone, for medical abortion. (2) The French and American summaries of product characteristics, based on data submitted to the relevant regulatory agencies, mention no teratogenicity in animals. However, some studies showed malformations in rats and rabbits. (3) Severe malformations have been reported in countries where misoprostol is frequently used for abortion without medical supervision despite its poor efficacy when used alone. The malformations included cranial nerve defects (especially pairs 6 and 7, characteristic of the M?bius syndrome) and various limb abnormalities. (4) Malformations, including one case of M?bius syndrome, have been reported in France after medically supervised use of misoprostol. (5) In practice, when a patient wishes to continue a pregnancy after a failed attempt at drug-induced abortion, she needs to be informed of the risk to her unborn child. Cranial nerve defects are rarely detectable by sonography, however thorough. In addition, misoprostol has a negative risk-benefit balance in the prevention or treatment of gastro-duodenal ulcers in young women.     

Selective serotonin reuptake inhibitors and withdrawal symptoms: a review of the literature

There are accumulating reports of withdrawal symptoms emerging following the discontinuation of selective serotonin reuptake inhibitor antidepressants. This report summarizes published reports, characterizes the withdrawal syndrome, discusses potential mechanisms of withdrawal, and makes recommendations for prevention and management. A computerized search was conducted using MEDLINE (1985–1996) to retrieve all case reports and pertinent studies of antidepressant withdrawal. A total of 46 case reports and two drug discontinuation studies were retrieved. All of the selective serotonin reuptake inhibitors were implicated in withdrawal reactions with paroxetine most often cited in case reports. Withdrawal reactions were characterized most commonly by dizziness, fatigue/weakness, nausea, headache, myalgias and paresthesias. The occurrence of withdrawal did not appear to be related to dose or treatment duration. Symptoms generally appeared 1–4 days after drug discontinuation, and persisted for up to 25 days. Time of onset and duration of symptoms differed little among the agents. The pathophysiology/pharmacology of withdrawal is unclear but may involve multiple neurotransmitter systems. It is concluded that all of the SSRIs can produce withdrawal symptoms and if discontinued, they should be tapered over 1–2 weeks to minimize this possibility. Some patients may require a more extended tapering period. No specific treatment for severe withdrawal symptoms is recommended beyond reinstitution of the antidepressant with subsequent gradual tapering as tolerated. © 1997 John Wiley & Sons, Ltd.     

Safety of selective serotonin reuptake inhibitors in pregnancy

Psychiatric treatment with selective serotonin reuptake inhibitors (SSRIs) may be desirable or necessary during pregnancy; however, the benefit of these treatments must balance the benefits to the mother with any risk to the developing foetus. At the present time, the role of serotonin in normal central nervous system development, as well as the effects of altering serotonin transmission at critical periods of embryo development, remains to be further clarified. Depression has a high prevalence in pregnant women (around 10%) and approximately one-half of the pregnancies are unplanned, making necessary that physicians have to know the risks associated with the decision to use this kind of antidepressants during pregnancy. The effects of antidepressants in pregnancy could be classified in several main categories: the teratogenic possible effects; the effects on the normal development of the brain and neuropsychological functions; the effects on birth weight and/or early delivery; the risk of increased bleeding on the mother during delivery; the neuropsychological behaviour and adaptation after delivery, including not only neonatal withdrawal syndromes but also pain reactivity and increased parasympathetic cardiac modulation during recovery after an acute noxious event and in a wide range of neurobehavioural outcomes; and medium- to long-term effects in neurocognitive functions in those children. These areas are reviewed according to the most recent published cohort-controlled studies and prospective surveys regarding SSRIs use in pregnancy. The review tries to clarify the blurred aspects of the use of SSRI during pregnancy and to give sensible and up-to-dated guidelines for the treatment of psychiatric disorders with SSRI during pregnancy.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Background: In asthma small airways inflammation often persists despite inhaled corticosteroids therapy. Objective: To discuss the effects of ciclesonide, a newer inhaled corticosteroid on small airways inflammation and the reliability of some biomarkers of small airways inflammation in asthma. Methods and results: Evaluation of a study assessing the short-term effects of ciclesonide on small airways inflammation in patients with mild to moderate asthma. Conclusions: Ciclesonide could have beneficial effects on small airways inflammation and some of the outcome measures used as efficacy endpoints could represent possible biomarkers of small airways involvement in obstructive chronic respiratory diseases.     

Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats

Conditioned fear stress (CFS)-induced freezing behavior has been proposed as an animal model of anxiety. In the present study, freezing was used to determine the anxiolytic activity of selective serotonin reuptake inhibitors (SSRIs), which are reported to be clinically effective in anxiety disorders. The duration of freezing behavior was reduced by acute treatment with the SSRIs citalopram (1–10 mg/kg) and fluvoxamine (3–30 mg/kg). Acute treatment with the serotonin (5-HT)/noradrenaline (NA) mixed reuptake inhibitor milnacipran (3–30 mg/kg) also attenuated CFS-induced freezing, while acute treatment with the NA reuptake inhibitors maprotiline and ORG4428, and the dopamine (DA) reuptake inhibitor GBR12909 failed to alter CFS-induced freezing. These results indicate that facilitation of 5-HT availability in the brain produced by 5-HT reuptake inhibition reduces CFS-induced freezing behavior. CFS may be a useful model for detecting the anxiolytic potential of 5-HT reuptake inhibitors.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Selective serotonin reuptake inhibitors (SSRIs) are now generally regarded as effective and better tolerated alternatives to tricyclic antidepressants (TCAs) for the treatment of depression. SSRIs also seem to be as well tolerated as moclobemide, mirtazapine, venlafaxine, reboxetine and nefazodone and show comparable efficacy. Minor differences have been observed between some SSRIs and some of the newer antidepressants but these findings are far from conclusive. Widespread use of the SSRIs has highlighted some unforseen adverse effects associated with SSRIs, namely hyponatraemia, EPSE and sexual dysfunction. Overall, differences in efficacy and tolerability between individual SSRIs are small and clinically insignificant.