Early Selective Serotonin Reuptake Inhibitor Research Articles

Selective Serotonin Reuptake Inhibitors for the Prevention of Post-Stroke Depression: A Systematic Review and Meta-Analysis.

There are controversial data on the efficacy and safety profile of selective serotonin reuptake inhibitors (SSRIs) to prevent post-stroke depression (PSD). We performed a systematic search in MEDLINE and SCOPUS databases to identify randomized-controlled trials questioning the use of early SSRI therapy in the post-stroke population and its effect on PSD incidence. We included 6 studies with 6560 participants. We extracted the data on PSD occurrence in association with the treatment arm (SSRI versus placebo), as reported by each study. For safety analysis, we extracted the information on adverse events. A random-effects model was used to calculate the pooled relative risk estimates. Early SSRI therapy was associated with a significant reduction of PSD occurrence compared to placebo (10.4% versus 13.8%; relative risk: 0.75 [95% CI, 0.66–0.86]; absolute risk reduction: 3.4%). SSRI therapy increases the risk of bone fracture (RR 2.28 [95% CI, 1.58–3.30]) and nausea (RR 2.05 [95% CI, 1.10–3.82]) in the post-stroke population. Considering the risk-benefit ratio of early SSRI therapy in the post-stroke population, future research should identify high-risk patients for PSD to improve the risk-benefit consideration of this therapy for use in clinical practice.

Early escitalopram administration as a preemptive treatment strategy against spasticity after contusive spinal cord injury in rats

In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Among various pathological conditions underlying spasticity, upregulated expression of 5-HT receptors (5-HTR) on the spinal motor neurons due to 5-HT denervation is considered one of crucial factors for hyperexcitability of the spinal circuit. As a 5-HT signal modulator, selective serotonin re-uptake inhibitors (SSRIs) are ordinarily prescribed for diseases associated with 5-HT in the CNS, and are known for their ability to increase 5-HT levels as well as to desensitize 5-HTR. Here, we hypothesized that early SSRI administration as a preemptive treatment strategy would effectively prevent the onset of spasticity. We used a rat model of contusive SCI and administered escitalopram during the first 4 weeks after injury, which is the period required for spasticity development in rodent models. We performed a swimming test to quantify spastic behaviors and conducted the Hoffman reflex test as well as histological analyses for 5-HT2AR and KCC2 expressions. Four weeks of escitalopram administration suppressed spastic behaviors during the swimming test and reduced the population of spasticity-strong rats. Moreover, the treatment resulted in decreased immunoreactivity of 5-HT2AR in the spinal motor neurons. Result of the H-reflex test and membrane expression of KCC2 were not significantly altered. In summary, early escitalopram administration could prevent the onset of spastic behaviors via regulation of 5-HT system after SCI, but could not modulate exaggerated spinal reflex. Our results suggest a novel application of SSRIs for preventative treatment of spasticity.

Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models

The developmental impact of selective serotonin reuptake inhibitor (SSRI) and other antidepressant treatments during gestation and postpartum on anxiety and depression behaviors in offspring is unclear. This review focuses on how perinatal exposure to SSRI and other antidepressant may have long term consequences for these affective behaviors during early childhood and beyond. Outcomes vary and consideration is given to methodological factors related to how early SSRI exposure affects developments studied in rodent models such as: a) between pre- and early post-natal SSRI exposure, b) sex, c) experimental models of gestational maternal stress and d) impact of non-SSRI antidepressant medications. We will also review how multiple contextual factors (maternal caregiving and gene x environment interactions) may contribute to the effects of perinatal SSRI exposure and maternal mental illness on affective behaviors in children.

Selective serotonin reuptake inhibitors for functional independence and depression prevention in early stage of post-stroke: A meta-analysis.

The efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) for functional independence and depression prevention in early stage of post-stroke (within 1 month after stroke onset) are still unclear. Relevant randomized controlled trials (RCTs) comparing early SSRIs therapy with placebo were sought from PubMed, Cochrane Library, Medline, and Embase. Primary outcomes were functional independence and depression occurrence. Secondary outcomes contained the improvement of Fugl-Meyer motor scale (FMMS) score and adverse events. We used fixed or random effects model to pooled effect estimates. And we chose risk ratio (RR) or mean differences (MDs) with the 95% confidence intervals (CIs) for data analysis. We included 10 RCTs with total 5370 patients. The outcome of functional independence showed no significant difference between SSRIs and placebo group (RR, 1.28; 95% CI, 0.96-1.72; P = .10; I = 92%). However, depression occurrence differed significantly between these 2 groups, which favored SSRIs group (RR, 0.78; 95% CI, 0.67-0.90; P = .001; I = 23%). In addition, we observed that the side effects of SSRIs were seizure and nausea. Except psychiatric disorders/insanity rate was less in SSRIs group than placebo group (RR, 0.66; 95% CI, 0.48-0.90; P = .009) (I = 0%), other adverse events were revealed non-significant in our meta-analysis. Our meta-analysis revealed that early SSRIs therapy were effective to prevent post-stroke depression. However, SSRIs did not improve patient's post-stroke functional independence. In addition to increase the occurrence of seizure and nausea, SSRIs were relatively safe.

Differential consequences of early SSRI exposure upon the developing nervous system of Xenopus laevis

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for maternal depression, one of the most prevalent perinatal psychiatric conditions. Although the effects of maternal depression have been well‐characterized, there exists controversy over the adverse effects of SSRI use upon fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we narrowed our focus to investigating the outcomes of exposure to the widely‐used SSRIs fluoxetine (Prozac) and citalopram (Celexa) upon the developing nervous system through behavioral and electrophysiological assays in Xenopus laevis. Exposure concentrations and timelines in humans were translated to the X. laevis using standard dosages and dose‐response curves. Behavioral assays and whole‐cell patch‐clamp recording were performed at full maturation (stage 49). The behavioral paradigms of acoustic startle habituation and seizure susceptibility in pentylenetetrazol have established relevance to autism‐like phenotypes in X. laevis and normal neurodevelopment. Interestingly, the two SSRIs demonstrated differential abnormalities in behavior and properties of the neuron and synaptic transmission. Administration of fluoxetine during development resulted in slower habituation and increased seizure susceptibility, while exposure to citalopram led to faster habituation and decreased seizure susceptibility. We sought to explain these opposing behavioral phenotypes by whole‐cell patch‐clamp recording from the sensory‐processing tectum. We found that tectal neurons from fluoxetine‐treated animals demonstrated increased intrinsic excitability and those from citalopram‐treated animals showed decreased excitability. Moreover, citalopram‐treated neurons had increased spontaneous excitatory post‐synaptic current episodes, indicating stronger individual synaptic transmission and stronger synaptic drive. Neither group showed altered synaptic facilitation, a neurobiological mechanism related to plasticity and learning, nor an imbalance of excitatory and inhibitory projections, a circuit‐level property associated with normal neurodevelopment. These results not only support the potential role of SSRIs upon the developing brain at both the behavioral and biological levels, but complicate the discretion to administer either antidepressant. Our findings implicate the off‐target effects of fluoxetine to explain such opposing consequences, given the higher selectivity of citalopram for the serotonin reuptake transporter. Future studies will systematically probe other monoamine transporters, including those for norepinephrine and dopamine, and serotonin receptors, both of which are affected by fluoxetine. This project was funded by the American Physiological Society.Support or Funding InformationThe American Physiological SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early Selective Serotonin Reuptake Inhibitors for Recovery after Stroke: A Meta-Analysis and Trial Sequential Analysis

Potential benefits and risks of early (≤30 days from stroke onset) selective serotonin reuptake inhibitors (SSRIs) treatment for neurologic functional recovery after stroke are not fully understood. We searched PubMed, Embase, and the Cochrane Library to identify randomized controlled trials that assessed SSRI medications during the initial ictus after stroke versus placebo. Primary outcome was decrease in National Institutes of Health Stroke Scale (NIHSS) score. Secondary outcomes included the improvement of Barthel index, functional independence (modified Rankin Scale score 0-2 at the end of follow-up), the incidence of depression, and adverse events including diarrhea, insomnia, hepatic enzyme disorders, seizure, and intracranial hemorrhage. We used fixed effects models or random effects models to estimate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) according to heterogeneity. Eight trials were included, with 1549 patients. Compared with placebo, decrease in NIHSS was greater in SSRI-treated patients (WMD, 0.82; 95% CI, 0.31-1.33; P = .002). Trial sequential analysis showed that the cumulative z curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. Early SSRI treatment also promoted Barthel index (WMD, 5.32; 95% CI, 1.65-8.99; P = .005) and functional independence (RR, 2.54; 95% CI, 1.82-3.55; P < .0001). There was no difference in the incidence of depression and adverse events between groups. No evidence of publication bias was detected. The early SSRIs treatment reduces the defective neurologic function in patients undergoing rehabilitation after stroke.

Effect of Citalopram on Emotion Processing in Humans: A Combined 5-HT1A [11C]CUMI-101 PET and Functional MRI Study

A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to have a critical role in affect processing. Thus we investigated the effect of acute citalopram on emotional processing and the relationship between DRN 5-HT1A receptor availability and amygdala reactivity. Thirteen (mean age 48±9 years) healthy male subjects received either a saline or citalopram infusion intravenously (10 mg over 30 min) on separate occasions in a single-blind, random order, crossover design. On each occasion, participants underwent a block design face-emotion processing task during fMRI known to activate the amygdala. Ten subjects also completed a positron emission tomography (PET) scan to quantify DRN 5-HT1A availability using [11C]CUMI-101. Citalopram infusion when compared with saline resulted in a significantly increased bilateral amygdala responses to fearful vs neutral faces (left p=0.025; right p=0.038 FWE-corrected). DRN [11C]CUMI-101 availability significantly positively correlated with the effect of citalopram on the left amygdala response to fearful faces (Z=2.51, p=0.027) and right amygdala response to happy faces (Z=2.33, p=0.032). Our findings indicate that the initial effect of SSRI treatment is to alter processing of aversive stimuli and that this is linked to DRN 5-HT1A receptors in line with evidence that 5-HT1A receptors have a role in mediating emotional processing.

Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory.

Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterised by fear extinction dysfunction in which fear circuit monoamines are possibly associated. PTSD often coexists with depressive/anxiety symptoms, and selective serotonin reuptake inhibitors (SSRIs) are recommended to treat PTSD. However, therapeutic mechanisms of SSRIs underlying the PTSD fear symptoms remain unclear. Using a rodent PTSD model, we examined the effects of early SSRI intervention in mood and fear dysfunctions with associated changes of monoamines within the fear circuit areas. A 14-day escitalopram (ESC) regimen (5mg/kg/day) was undertaken in two separate experiments in rats which previously received a protocol of single prolonged stress (SPS). In experiment 1, sucrose preference and elevated T-maze were used to index anhedonia depression and avoidance/escape anxiety profiles. In experiment 2, the percentage of freezing time was measured in a 3-day fear conditioning paradigm. At the end of our study, tissue levels of serotonin (5-HT) in the medial prefrontal cortex, amygdala, hippocampus, and striatum were measured in experiment 1, and the efflux levels of infralimbic (IL) monoamines were measured in experiment 2. In experiment 1, ESC corrected both behavioural (depression/anxiety) and neurochemical (reduced 5-HT tissue levels in amygdala/hippocampus) abnormalities. In experiment 2, ESC was unable to correct the SPS-impaired retrieval of fear extinction. In IL, ESC increased the efflux level of 5-HT but failed to reverse SPS-reduced dopamine (DA) and noradrenaline (NA). PTSD-induced mood dysfunction is psychopathologically different from PTSD-induced fear disruption in terms of disequilibrium of monoamines within the fear circuit areas.

Effect of soothing-liver and nourishing-heart acupuncture on early selective serotonin reuptake inhibitor treatment onset for depressive disorder and related indicators of neuroimmunology: a randomized controlled clinical trial

ObjectiveTo observe the effect of soothing-liver and nourishing-heart acupuncture on selective serotonin reuptake inhibitor (SSRIs) treatment effect onset in patients with depressive disorder and related indicators of neuroimmunology. MethodsOverall, 126 patients with depressive disorder were randomly divided into a medicine and acupuncture-medicine group using a random number table. Patients were treated for 6 consecutive weeks. The two groups were evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS) and Side Effects Rating Scale (SERS) to assess the effect of the soothing-liver and nourishing-heart acupuncture method on early onset of SSRI treatment effect. Changes in serum 5-hydroxytryptamine (5-HT) and inflammatory cytokines before and after treatment were recorded and compared between the medicine group and the acupuncture-medicine group. ResultsThe acupuncture-medicine group had significantly lower MADRS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). The acupuncture group had significantly lower SERS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). At 6 weeks after treatment, serum 5-HT in the acupuncture-medicine group was significantly higher compared with the medicine group (P < 0.01). Interleukin-6 (IL-6) in the acupuncture-medicine group was significantly lower than that in the medicine group (P < 0.01), whereas there was no significant difference in IL-1β between the groups (P > 0.05). Anti-inflammatory cytokines IL-4 and IL-10 were significantly higher in the acupuncture-medicine group compared with the medicine group (P < 0.01, P < 0.05, respectively). ConclusionThe soothing-liver and nourishing-heart acupuncture method can effectively accelerate the onset of SSRI effects when treating depressive disorder and can significantly reduce the adverse reactions of SSRIs. Moreover, acupuncture can enhance serum 5-HT and regulate the balance of pro-inflammatory cytokines and anti-inflammatory cytokines.

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for pediatric major depressive disorder (MDD). We conducted a meta-analysis to examine the following: the time-course of response to SSRIs in pediatric depression; whether higher doses of SSRIs are associated with an improved response in pediatric depression; differences in efficacy between SSRI agents; and whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD. We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo groups. The meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating that the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data (log[week]= 0.10, 95% CI= 0.06-0.15, p< .0001). There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD. Treatment gains in pediatric MDD are greatest early in treatment and are, on average, minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response (e.g., 2-4 weeks) to predict outcomes in short-term pharmacological trials.

Which adverse effects influence the dropout rate in selective serotonin reuptake inhibitor (SSRI) treatment? Results for 50,824 patients.

Background: Nowadays, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants due to their superior clinical efficacy, effectiveness, tolerability, and safety as compared to tricyclic antidepressants or monoamino oxidase inhibitors. However, despite these advantages SSRIs are still associated with a number of adverse drug reactions, especially in the early stages of treatment, which may lead to premature discontinuation of therapy in some cases. The aim of the present study was to assess the most common adverse drug reactions of SSRIs as well as their impact on dropout rate in a large study population.Patients and methods: Data for 50,824 patients treated for major depressive disorder with SSRIs for the first time was accessed via the Disease Analyzer database (IMS Health, Germany), providing information on SSRI adverse drug reactions and their influence on premature treatment discontinuation calculated by regression analysis. The presence of certain co-morbidities was also registered. Results: The mean age was 54.5 ± 19 years, two-thirds of the study population being female. The adverse effects mentioned most frequently were: “discomfort” of the digestive system (10%), sleep disorders (8.6%), and heart rhythm disorders (4%); however, these were of tolerable severity as they did not significantly influence the dropout rate. Contrary to that, somnolence and younger age (≤50 years) in particular increased the chance of premature treatment discontinuation, while patients suffering from cardiovascular risk factors or osteoporosis tended to adhere to the therapy.Conclusions: Overall, there is high tolerability for early SSRI treatment, whereas the occurrence of somnolence leads to discontinuation.

Paradoxical effects of short-term antidepressant treatment in fMRI emotional processing models in volunteers with high neuroticism

Short-term antidepressant administration has been reported to decrease amygdala response to threat in healthy volunteers and depressed patients. Neuroticism (N) is a risk factor for depression but has also been associated with slow or incomplete remission with antidepressant drug treatment. Our aim was to investigate early selective serotonin reuptake inhibitor (SSRI) administration neural effects on implicit processing of fearful facial expressions in volunteers with high levels of N. Highly neurotic subjects received 20 mg/day citalopram versus placebo for 7 days in a double-blind, between-groups design. On the last day haemoperfusion and functional magnetic resonance imaging (fMRI) data during a gender discrimination task with fearful and happy faces were acquired. A control group of non-neurotic volunteers was also tested. High-N volunteers had reduced responses to threatening facial expressions across key neural circuits compared to low-N volunteers. SSRI treatment was found to elevate resting perfusion in the right amygdala, increase bilateral amygdalae activation to positive and negative facial expressions and increase activation to fearful versus happy facial expressions in occipital, parietal, temporal and prefrontal cortical areas. These results suggest that 7 days of SSRI administration can increase neural markers of fear reactivity in subjects at the high end of the N dimension and may be related to early increases in anxiety and agitation seen early in treatment. Such processes may be involved in the later therapeutic effects through decreased avoidance and increased learning about social 'threat' cues.

Neonatal fluoxetine exposure affects the action potential properties and dendritic development in cortical subplate neurons of rats

Selective serotonin reuptake inhibitor (SSRI)-type antidepressants might be given to depressive pregnant women and the developing fetuses are thus exposed to these drugs. Since serotonin plays important roles in the maturation of the nervous system, early SSRI exposure might influence the fetal brain development. To test this hypothesis, we treated the neonatal rat pups with fluoxetine (Flx) from the day of birth to postnatal day (P) 4, comparable to the third trimester of human gestation, and observed the physiological and morphological features of subplate neurons (SPns), a group of cells important for early cortical development and vulnerable to neonatal neural insults. Using whole-cell patch-clamp recording technique, we examined the passive membrane properties and characteristics of action potential (AP). In SPns of Flx-treated rats, the rheobase for generating an AP was increased and the width of APs was reduced, especially in the falling phase. In the morphological aspect, the dendritic remodeling of SPns including dendritic branching, elongation and pruning were affected by early Flx treatment. Together, our results demonstrate that the teratogenic effect of early SSRI exposure on the structure and function of developing SPns and these changes may lead to undesired brain activity and distorted behaviors later in life.

Impact of antidepressant dispensing on health service use among veterans with stroke

To examine the association between dispensing of a selective serotonin reuptake inhibitor (SSRI) antidepressant medication and inpatient and outpatient service use in a cohort of veterans with confirmed acute stroke. Retrospective study. Southeastern U. S. Veterans Health Administration (VHA) network, from October 1, 2000, to September 30, 2001. 785 veterans with confirmed acute stroke. VHA and Medicare databases were used to obtain outcome information during the 12 months after the index stroke date. Number of inpatient admissions, length of inpatient stays, and number of outpatient clinic stops for all causes. Among the study cohort (n = 785), 12% had an SSRI dispensed 30 days or less poststroke, 19% had an SSRI dispensed between 31 and 365 days poststroke, and 69% were not dispensed an SSRI poststroke. After adjusting for risk factors, no significant association was found between time to first SSRI dispensing and inpatient use. However, patients with an early SSRI dispensing were more likely to have a greater number of all-cause outpatient stops compared with patients with later or no SSRI dispensing. Regardless of time to first dispensing, patients dispensed an SSRI had more outpatient clinic stops than patients without the medication. SSRI dispensing was not predictive of inpatient use but was a strong predictor of all-cause outpatient clinic stops.

SSRI-Enhanced Locus Coeruleus Activity and Adolescent Suicide: Lessons from Animal Models

SSRI-Enhanced Locus Coeruleus Activity and Adolescent Suicide: Lessons from Animal Models

Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care

Background This study aimed to identify the predictors and outcomes of SSRI antidepressant continuation, discontinuation and switching over a 9-month period of naturalistic observation. Methods Primary care patients ( n=573) with physician-diagnosed depression from 37 practices were randomized to an open-label trial of one of three selective serotonin reuptake inhibitors (SSRIs) managed in their primary care setting. Psychiatric characteristics and treatment course were assessed at baseline and at 1, 3, 6 and 9 months after medication initiation. Results Nineteen percent of patients switched SSRIs, which occurred significantly sooner than discontinuation (median: 41 vs. 100 days). Time to discontinuation was primarily explained by baseline patient skepticism about taking an antidepressant (62% increase in discontinuation risk). In contrast, time to switch was associated with greater impairment at baseline and lesser improvement in impairment during the first month on medication. Patients who discontinued were significantly less likely to be depressed 9 months after starting medication than those who either continued or switched medication, and were less symptomatic and impaired than patients who switched. Conclusions Baseline impairment may increase the risk for SSRI antidepressant switching. Additionally, patient skepticism about antidepressants predicts early SSRI discontinuation and may predict rapid recovery. Intent-to-treat analyses in nonrandomized clinical trials may paradoxically inflate antidepressant effect sizes.

Pain Reactivity in 2-Month-Old Infants After Prenatal and Postnatal Selective Serotonin Reuptake Inhibitor Medication Exposure

In this prospective study, we examined biobehavioral responses to acute procedural pain at 2 months of age in infants with prenatal and postnatal selective serotonin reuptake inhibitor (SSRI) medication exposure. Based on previous findings showing reduced pain responses in newborns after prenatal exposure, we hypothesized that altered pain reactivity would also be found at 2 months of age. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the respiratory activity and heart rate variability (HRV) responses to a painful event (heel-lance) were compared between 3 groups of infants: (1) infants with prenatal SSRI exposure alone (n = 11; fluoxetine, n = 2; paroxetine, n = 9); (2) infants with prenatal and postnatal SSRI (via breast milk) exposure (total n = 30; fluoxetine, n = 6; paroxetine, n = 20; sertraline, n = 4); and (3) control infants (n = 22; nonexposed) during baseline, lance, and recovery periods. Measures of maternal mood and drug levels were also obtained, and Bayley Scales of Infant Development-II were administered at ages 2 and 8 months. Facial action increased in all groups immediately after the lance but was significantly lower in the pSE group during the lance period. HR among infants in the pSE and ppSE groups was significantly lower during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, exposed infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in control infants. Although postnatal exposure via breast milk was extremely low when infant drug levels could be detected in ppSE infants, changes in HR and HRV from lance to recovery were greater compared among infants with levels too low to be quantified. Neither maternal mood nor the presence of clonazepam influenced pain responses. Blunted facial-action responses were observed among infants with prenatal SSRI exposure alone, whereas both prenatal and postnatal exposure was associated with reduced parasympathetic withdrawal and increased parasympathetic cardiac modulation during recovery after an acute noxious event. These findings are consistent with patterns of pain reactivity observed in the newborn period in the same cohort. Given that postnatal exposure via breast milk was extremely low and altered biobehavioral pain reactivity was not associated with levels of maternal reports of depression, these data suggest possible sustained neurobehavioral outcomes beyond the newborn period. This is the first study of pain reactivity in infants with prenatal and postnatal SSRI exposure, and our findings were limited by the lack of a depressed nonmedicated control group, small sample size, and understanding of infant behaviors associated with pain reactivity that could have also have been influenced by prenatal SSRI exposure. The developmental and clinical implications of our findings remain unclear, and the mechanisms that may have altered 5-hydroxytryptamine-mediated pain modulation in infants after SSRI exposure remain to be studied. Treating maternal depression with antidepressants during and after pregnancy and promoting breastfeeding in this setting should remain a key goal for all clinicians. Additional study is needed to understand the long-term effects of prenatal and early postnatal SSRI exposure.

Making advances where it matters: improving outcomes in mood and anxiety disorders.

Mood and anxiety disorders are among the most prevalent psychiatric illnesses and are associated with considerable morbidity and mortality. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective treatments for major depression and anxiety disorders, and have become the most widely prescribed antidepressants worldwide. However, several issues limit SSRI treatment outcomes. Although SSRIs have a wider therapeutic margin and a milder side-effect profile compared to earlier antidepressants, even minor SSRI side effects can have a major impact on treatment outcomes by interfering with patient compliance. Nausea is one of the most common early SSRI side effects, and advances in SSRI delivery systems can diminish this. A controlled-release formulation of paroxetine targets the site of absorption for a more distal region of the small intestine, thereby avoiding the stimulation of upper gastrointestinal serotonin receptors that mediate nausea. The sustained-release characteristics also reduce the amplitude in blood level peaks and troughs, which may lead to diminished side effects and enhanced efficacy. Sexual side effects and weight gain are important sustained SSRI side effects, which affect compliance during continuation and maintenance phases of treatment. Several strategies address SSRI sexual side effects, including the use of adjunctive medication and/or manipulations in the scheduling of drug administration. Depression negatively impacts the management of many medical illnesses, including cardiovascular disease, cancer, and infectious diseases. The recognition and treatment of depression leads to improved outcomes in the management of breast cancer. Prophylactic SSRI treatment significantly reduces the incidence of interferon-associated depression and enhances completion rates in malignant melanoma.