The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders

Approximately 10% of pregnant women are prescribed antidepressant drugs (ADDs), with selective serotonin reuptake inhibitors (SSRIs) the most widely prescribed. SSRIs bind to the serotonin transporter (SERT), blocking the reabsorption of serotonin by the presynaptic neuron and increasing serotonin levels in the synaptic cleft. The serotonergic system regulates a range of brain development processes including neuronal proliferation, migration, differentiation and synaptogenesis. Given the presence of SERT in early brain development, coupled with the ability of SSRIs to cross the placenta and also enter breast milk, concerns have been raised regarding the effects of SSRI exposure on the developing foetus and newborns. In this review, we evaluate preclinical and clinical studies that have examined the effects of maternal SSRI exposure and the risk for altered neurodevelopment and associated behaviours in offspring. While the current body of evidence suggests that maternal SSRI treatment may cause perturbations to the neurobiology, behaviour and ultimately risk for neurodevelopmental disorders in exposed offspring, conflicting findings do exist and the evidence is not conclusive. However, given the increasing incidence of depression and number of women prescribed ADDs during pregnancy, further investigation into this area is warranted.     

Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5-hydroxytryptamine, 5-HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5-HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non-human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5-HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5-HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5-HT uptake; prescribed SSRIs appear to exert similar effects on 5-HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5-HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.     

The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents: A review

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is widely prescribed for the treatment of depression and anxiety-related disorders. While extensive research has established that fluoxetine is safe for adults, safety is not guaranteed for (unborn) children and adolescents. Some clinical studies have reported adverse outcomes, such as premature birth, neonatal cardiovascular abnormalities, and pulmonary hypertension in children whose mothers used SSRIs during pregnancy. In addition, several reports show that adolescent fluoxetine treatment increases risk for suicidal behavior. Despite these studies, fluoxetine is not contraindicated in the treatment of depressed pregnant women and adolescents. Longitudinal research in humans is limited because of ethical reasons and time constraints, and to overcome these limitations, rodents are used to increase insight in the age-dependent effects of fluoxetine exposure. It has been established that neonatal and adolescent fluoxetine exposure leads to paradoxical anxiety- and depression-like features in later life of rats and mice, although in some studies adolescent fluoxetine exposure was without effects. These age-dependent outcomes of fluoxetine may be explained by serotonin's neurotrophic effects, which may vary according to the developmental stage of the brain due to epigenetic modifications. Here we review the existing evidence for the age-dependent effects of fluoxetine in humans and rodents, address the gaps in our current knowledge and propose directions for future research. Given the overlap between human and rodent findings, rodents provide heuristic value in further research on the age-dependent effects of SSRIs.     

Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies

This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case–control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case–control studies were 2.13 (95% CI 1.66–2.73) and 1.81 (95% CI 1.47–2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.     

Antidepressants and suicide: risk-benefit conundrums

There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. To shed light on this issue, this paper reviews available randomized controlled trials (RCTs), meta-analyses of clinical trials and epidemiological studies that have been undertaken to investigate the issue further. The original clinical studies raising concerns about SSRIs and suicide induction produced evidence of a dose-dependent link on a challenge-dechallenge and rechallenge basis between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicated that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, revealed an excess of suicidal acts on active treatments compared with placebo, with an odds ratio of 2.4 (95; confidence interval 1.6-3.7). This excess of suicidal acts also appears in epidemiological studies. The data reviewed here make it difficult to sustain a null hypothesis that SSRIs do not cause problems in some individuals. Further studies or further access to data are indicated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.     

The adverse skeletal effects of selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are a widely used group of antidepressants (ADs) with reported potential detrimental effects on bone mineral density (BMD) and increased fracture risk. Here, a comprehensive review of the in vitro, in vivo and clinical studies to date was carried out using the medical search engines MEDLINE (1950 to September 2010) and EMBASE (1980 to September 2010). Serotonin (5-HT) receptors have been identified on osteoclast, osteoblast and osteocyte cell lines. The effect of SSRIs on bone formation and resorption appears to be governed by the activation of a number of 5-HT receptors on osteoblasts and osteoclasts via endocrine, autocrine/paracrine and neuronal pathways. In vitro, in vivo and clinical collective data appears to indicate that SSRIs have a negative effect on bone at the therapeutic dose levels widely used for the treatment of depression in current clinical practice. Caution may therefore have to be employed with the use of SSRIs in patients at an increased risk of falls and osteoporosis. Further studies are needed in order to fully elicit the role of SSRIs in bone formation and their effects in the low oestrogen state.     

Developmental effects of SSRIs: lessons learned from animal studies.

Selective serotonin reuptake inhibitors (SSRIs) are utilized in the treatment of depression in pregnant and lactating women. SSRIs may be passed to the fetus through the placenta and the neonate through breastfeeding, potentially exposing them to SSRIs during peri- and postnatal development. However, the long-term effects of this SSRI exposure are still largely unknown. The simplicity and genetic amenability of model organisms provides a critical experimental advantage compared to studies with humans. This review will assess the current research done in animals that sheds light on the role of serotonin during development and the possible effects of SSRIs. Experimental studies in rodents show that administration of SSRIs during a key developmental window creates changes in brain circuitry and maladaptive behaviors that persist into adulthood. Similar changes result from the inhibition of the serotonin transporter or monoamine oxidase, implicating these two regulators of serotonin signaling in developmental changes. Understanding the role of serotonin in brain development is critical to identifying the possible effects of SSRI exposure.     

Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects

Gentile S. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects. Objective: To assess the methodological value of studies that signaled one or more selective serotonin reuptake inhibitors (SSRIs) as teratogenic agents. Method: Medical literature, published in English (1980–November 2010), was searched using MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library to identify all articles, reporting primary data that suggested any increased rate of congenital malformations following prenatal exposure to SSRIs as a group or single SSRI agents. Results: Reviewed studies showed some severe methodological limitations, such as data coming from retrospective studies and incomplete information available with reference to timing of exposure and dosages. Further, data continue to be extrapolated from automated databases that do not declare whether the women reported actually used the prescribed medication. Further, it should be noted the distinct lack of research analysis available with reference to the potential impact of non‐iatrogenic confounders on pregnancy. Conclusion: In light of such considerations, the hypothesized teratogenicity of SSRIs remains undemonstrated. Hence, further, well‐designed research is needed to differentiate definitively the detrimental impact of depression on pregnancy outcomes from potential iatrogenic events.     

The use of selective serotonin reuptake inhibitors in autism and related disorders

This paper reviews the published literature on the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of symptoms associated with autistic disorder and other pervasive developmental disorders (PDDs) in both children and adults. To date, placebocontrolled studies of SSRIs have involved only fluvoxamine (in children and adults) and fluoxetine (in children). Open-label and retrospective studies of all other SSRIs in PDDs have also been published that suggest effectiveness. Despite these positive reports, there continues to be questions about the tolerability and appropriate dosing of SSRIs in children with PDDs. Because of the limited number of placebo-controlled studies, definitive conclusions about the role SSRIs should play in the clinical treatment of children with PDDs cannot be drawn. Larger, placebo-controlled studies of SSRIs are needed to guide clinical treatment.     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?

OBJECTIVE: We review evidence on two claims that have been made about the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants; that they have: (i) decreased suicide rates in the population; and (ii) increased suicide rates in some individuals early in treatment. METHOD: We critically review evidence in the English-speaking peer-reviewed medical literature on: (i) meta-analyses of randomized controlled trials (RCTs) of SSRIs; (ii) observational studies of suicide risk in patients prescribed SSRIs and other antidepressants; and (iii) ecological studies of correlations between population use of SSRI use and population suicide rates. RESULTS: The largest and most recent meta-analyses of RCTs of SSRIs have found suggestive evidence that SSRIs increase suicidal ideation early in treatment compared with placebo. Observational studies have found an increased risk of self-harm within 9 days of an antidepressant drug being prescribed but the risk has been similar for the older tricyclic antidepressants and the SSRIs. Ecological studies in developed countries have found either that suicide rates have declined as SSRI use has increased, or have found no relationship between suicide rates and increased SSRI use. CONCLUSIONS: Meta-analyses of RCTs suggest that SSRIs increase suicide ideation compared with placebo but the observational studies suggest that SSRIs do not increase suicide risk more than older antidepressants. If SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.     

Treatment of severe depression with the selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population. Depression and Anxiety 4:182–189, 1996/1997. © 1997 Wiley-Liss, Inc.     

Selective serotonin reuptake inhibitors and risk reduction for cardiovascular disease in patients with schizophrenia: A controversial but promising approach

Patients with schizophrenia (SCZ) are at high risk of cardiovascular disease (CVD) due to an inherited predisposition, a sedentary life style and the use of antipsychotic medications. Several approaches have been taken to minimize this risk but results continue to be unsatisfactory. A potential alternative is prescribing selective serotonin reuptake inhibitors (SSRIs). SSRIs decrease platelet aggregation and reduce the risk of coronary heart disease in patients with depression. We therefore aim to investigate whether there is evidence that supports the use of SSRIs to reduce the risk for CVD in SCZ. A review of the literature revealed five published reports relating to the impact of SSRIs on CV risk in SCZ. Three trials assessed the influence on metabolic parameters of fluvoxamine when combined with clozapine. Two of those studies found improvements with fluvoxamine. Of the other two reports, one indicates SSRIs as a group caused minimal but statistically significant increments in total cholesterol, low-density lipoprotein and triglyceride. The second report suggests that when SSRIs are combined with antipsychotics, the metabolic impact depends on the antipsychotic prescribed. While there are promising results, no conclusions can be made currently on whether SSRIs increase or decrease CV risk in SCZ. Further studies are needed to resolve this matter.     

Preclinical antiepileptic actions of selective serotonin reuptake inhibitors--implications for clinical trial design

Selective serotonin reuptake inhibitors (SSRIs) can reduce seizure frequency in humans, but no large-scale clinical trials have been done to test the utility of SSRIs as potential antiepileptic drugs. This may be caused in part by a small number of reports on seizures triggered by SSRI treatment. The preclinical literature on SSRIs is somewhat conflicting, which is likely to contribute to the hesitance in accepting SSRIs as possible anticonvulsant drug therapy. A careful review of preclinical studies reveals that SSRIs appear to have region-specific and seizure subtype-specific effects, with models of chronic partial epilepsy being more likely to respond than models of acute generalized seizures. Moreover, this preclinical profile is similar to that of clinical antiepileptic drugs. These observations suggest that SSRIs are promising antiepileptic agents, and that clinical trials may benefit from defining patient groups according to the underlying pathology.     

Effects of nortriptyline and paroxetine on postural sway in depressed elderly patients.

Tricyclic antidepressants (TCAs) have previously been found to be related to an increased incidence of falls in elderly persons. Recent pharmacoepidemiologic and nursing home studies have suggested that the risk of falls and fractures in elderly patients receiving selective serotonin reuptake inhibitors (SSRIs) is not different from that of patients receiving TCAs. The authors therefore evaluated postural sway in an older population of depressed patients randomly assigned to treatment with either nortriptyline or paroxetine and did not find any change in postural sway after 6 weeks' treatment with either antidepressant. Further studies with other SSRIs are needed.     

Bone Mineral Density in Adolescents With Eating Disorders Exposed to Selective Serotonin Reuptake Inhibitors

Retrospective chart review was used to collect data from adolescents seen in a specialized eating disorder program over an 11-year period in order to investigate any association between exposure to selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD). SSRI users were matched with controls based on age (within 1.5 years), gender, eating disorder diagnosis, and percent ideal body weight (within 5%), resulting in a sample of 31 pairs. SSRI users had significantly lower BMD z-scores, compared to controls (–1.094 vs. –0.516, p < .035), suggesting that exposure to SSRIs may be a risk factor for lowered BMD.     

The opposite effects of fluvoxamine and sertraline in the treatment of psychotic major depression: a case report

Background  

Psychotic major depression is a clinical subtype of major depressive disorder. A number of clinical studies have demonstrated the efficacy of the combination of an antidepressant (for example, a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI)) and an atypical antipsychotic or electroconvulsive therapy (ECT) in treating psychotic major depression. In several studies, monotherapy of SSRIs such as fluvoxamine has been shown to be effective in the treatment of psychotic major depression.     

The use of biomarkers in psychiatric research: how serotonin transporter occupancy explains the dose-response curves of SSRIs

This column reviews why signal detection in psychiatric research has been problematic, how the use of biomarkers can help, how and why fixed dose studies are done, and how these studies differ from what clinicians do in practice. The fixed dose studies done with selective serotonin reuptake inhibitors (SSRIs) are used to illustrate general points about clinical trial research methodology relevant to clinical practice. Studies with SSRIs have yielded flat dose-response curves with regard to efficacy but ascending dose-response curves with regard to discontinuation due to adverse effects. These clinical trial findings are explained by studies using serotonin transporter inhibition or occupancy as a surrogate marker for SSRI efficacy and tolerability. Initially, these studies were conducted ex vivo using human platelets as the model system; however, they have now been extended to in vivo measurement of serotonin transporter occupancy in patients using positron emission tomography. The conclusion from this work is that the usually effective, minimum dose of each marketed SSRI produces 70%-80% inhibition or occupancy (depending on the methodology used) of the serotonin transporter; higher rates of inhibition or occupancy do not on average increase efficacy but instead increase early discontinuation rates due to adverse effects. These increased discontinuation rates offset any gain in efficacy when the results are analyzed using the last-observation-carried-forward approach. An understanding of these principles also provides an explanation for what initially may appear to be a conundrum: why some patients can benefit from a dose increase even though, in fixed dose clinical trials, the drug had a flat dose-efficacy curve.     

Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin

Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown. In this work, we use fast in vivo serotonin measurement tools to investigate the nexus between serotonin, inflammation, and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus. We show that these decreased serotonin levels are supported by increased histamine activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability of escitalopram to augment extracellular serotonin is impaired because of an off-target action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular serotonin levels following LPS. This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression.SIGNIFICANCE STATEMENT Acute LPS-induced inflammation (1) increases CNS histamine, (2) decreases CNS serotonin (via inhibitory histamine receptors), and (3) prevents a selective serotonin reuptake inhibitor (SSRI) from effectively increasing extracellular serotonin. A targeted depletion of histamine recovers SSRI-induced increases in extracellular hippocampal serotonin.     

Pooling pharmacogenetic studies on the serotonin transporter: a mega-analysis

Pharmacogenetic studies on antidepressants have reported an association between the promoter of the serotonin transporter gene (SERTPR) and response to antidepressant treatment. In the present study, individual subject data from three pharmacogenetic studies on SERTPR were pooled ('mega-analysis') to investigate the role of this gene in the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs). A group of 548 patients who were treated with different SSRIs in a double blind design were included; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. SERPR allelic variants were determined in each subject using a PCR-based technique. In the whole sample, subjects with SERPR() l/l variants showed a significantly better response to treatment, and this effect was independent from analyzed demographic and clinical variables but was not uniform across samples. This result supports the involvement of the SERTPR gene in response to antidepressant treatments.