Perinatal citalopram exposure selectively increases locus ceruleus circuit function in male rats

Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), have been widely prescribed for major depressive disorder, not only for adult populations, but also for children and pregnant mothers. Recent evidence suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels in the raphe system and decreases norepinephrine (NE) locus ceruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long-lasting downregulation of the 5-HT-raphe system, which is opposite to that seen with chronic adult treatment. Therefore, the goal of the present investigation was to test the hypothesis that perinatal CTM exposure (20 mg/kg/d) from postnatal day 1 (PN1) to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). Our single-neuron LC electrophysiological data demonstrated an increase in spontaneous and stimulus-driven neural activity, including an increase in phasic bursts in CTM-exposed animals. In addition, we demonstrated a corresponding immunoreactive increase in the rate-limiting catalyzing catecholamine enzyme (tyrosine hydroxylase) within the LC and their neocortical target sites compared to saline controls. Moreover, these effects were only evident in male exposed rats, suggesting a sexual dimorphism in neural development after SSRI exposure. Together, these results indicate that administration of SSRIs during a sensitive period of brain development results in long-lasting alterations in NE-LC circuit function in adults and may be useful in understanding the etiology of pervasive developmental disorders such as autism spectrum disorder.     

Selective serotonin-reuptake inhibitors: an update.

Selective serotonin-reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, represent an important advance in the pharmacotherapy of mood and other disorders. They are chemically unrelated to tricyclic, heterocyclic, and other first-generation antidepressants. SSRIs are the treatment of choice for many indications, including major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder, because of their efficacy, good side-effect profile, tolerability, and safety in overdose, as well as patient compliance. A review of the literature was conducted using Medline and the terms "SSRIs," "fluoxetine," "sertraline," "paroxetine," "fluvoxamine," and "citalopram." Articles were limited to those published in English within the last 15 years. The search revealed that indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder. One SSRI, fluoxetine, has demonstrated safety in pregnancy. Side effects of SSRIs include gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction.     

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Eating Disorders

Abstract

Objectives. The treatment of eating disorders is a complex process that relies not only on the use of psychotropic drugs but should include also nutritional counselling, psychotherapy and the treatment of the medical complications, where they are present. In this review recommendations for the pharmacological treatment of eating disorders (anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED)) are presented, based on the available literature. Methods. The guidelines for the pharmacological treatment of eating disorders are based on studies published between 1977 and 2010. A search of the literature included: anorexia nervosa bulimia nervosa, eating disorder and binge eating disorder. Many compounds have been studied in the therapy of eating disorders (AN: antidepressants (TCA, SSRIs), antipsychotics, antihistaminics, prokinetic agents, zinc, Lithium, naltrexone, human growth hormone, cannabis, clonidine and tube feeding; BN: antidepressants (TCA, SSRIs, RIMA, NRI, other AD), antiepileptics, odansetron, d-fenfluramine Lithium, naltrexone, methylphenidate and light therapy; BED: antidepressants (TCA, SSRIs, SNRIs, NRI), antiepileptics, baclofen, orlistat, d-fenfluramine, naltrexone). Results. In AN 20 randomized controlled trials (RCT) could be identified. For zinc supplementation there is a grade B evidence for AN. For olanzapine there is a category grade B evidence for weight gain. For the other atypical antipsychotics there is grade C evidence. In BN 36 RCT could be identified. For tricyclic antidepressants a grade A evidence exists with a moderate-risk-benefit ratio. For fluoxetine a category grade A evidence exists with a good risk-benefit ratio. For topiramate a grade 2 recommendation can be made. In BED 26 RCT could be identified. For the SSRI sertraline and the antiepileptic topiramate a grade A evidence exists, with different recommendation grades. Conclusions. Additional research is needed for the improvement of the treatment of eating disorders. Especially for anorexia nervosa there is a need for further pharmacological treatment strategies.     

Fluvoxamine in the treatment of anxiety disorders

Fluvoxamine is a selective-serotonin reuptake inhibitor (SSRI) that has proved effective in large double-blind, randomized, controlled trials involving patients with social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder. Improvements have also been demonstrated in patients with post-traumatic stress disorder, as well as those with a range of obsessive-compulsive spectrum disorders including binge eating disorder, bulimia nervosa, pathological gambling, and body dysmorphic disorder. Several well controlled studies have confirmed the efficacy of fluvoxamine in children and adolescents with OCD, SAD, and other anxiety disorders, and it was the first SSRI to be registered for the treatment of OCD in children. Fluvoxamine is well tolerated. In common with other SSRIs, the most frequently reported adverse event is nausea. Fluvoxamine does not cause sedation or cognitive impairment and is associated with a low risk of sexual dysfunction, suicidality, and withdrawal reactions. It is safe in overdose and has no significant effect on body weight or cardiovascular parameters.     

Topiramate for the treatment of kleptomania: a case series and review of the literature

Kleptomania--the inability to resist the impulse to steal objects, not for personal use or monetary gain--is currently classified in psychiatric nomenclature as an impulse control disorder. There is no standard pharmacologic therapy for this disorder. If kleptomania was considered a form of obsessive-compulsive disorder, treatments used for this spectrum, including serotonin reuptake inhibitors (SSRI), other antidepressants, opioid receptor antagonist medications, and mood stabilizers, could be logically tested. Topiramate is currently used for the treatment of patients with affective and compulsive eating disorders. This report documents three kleptomanic patients who responded well to topiramate given either alone or in combination with SSRIs.     

Depression treatment and maternal functioning

Background: In women with major depressive disorder (MDD), maternal role functioning is negatively impacted but has been shown to improve with treatment; however, most investigations have not included a control group or studied women longitudinally. We hypothesized that women with MDD who responded to serotonin selective reuptake inhibitors (SSRIs) would have overall functioning and maternal role functioning scores similar to that of the control group and superior to women with MDD (either untreated or nonresponsive to SSRIs). Methods: This prospective, longitudinal observational study (n = 215) included postpartum assessments at 2 1/2 weeks, 3 months, 6 months, and 12 months. Postpartum women were categorized into four mutually exclusive exposure groups by depression and medication status: (1) Control group (no SSRI, no MDD; (2) Responder (SSRI, no MDD); (3) Untreated (MDD, no SSRI); and (4) Nonresponder (Both MDD and SSRI). Outcome variables include a measure of overall functioning (Global Assessment Scale, GAS) and three measures of maternal role functioning (Maternal Self Efficacy, ICS; Gratification in Maternal Role, GRAT; and overall maternal role functioning, IFSAC). Results: The study hypothesis was supported. Responders had scores related to overall functioning and maternal role functioning that were similar to the control group and superior to nonresponders and untreated women with MDD, as measured by the GAS and the GRAT. Conclusion: Postpartum depression treatment optimally targets both symptom improvement and maternal functional recovery. The GRAT is a simple, self‐administered instrument that can be used with a depression measure to assess maternal role functioning. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.     

Persistent pulmonary hypertension of the newborn and selective serotonin reuptake inhibitors: lessons from clinical and translational studies

Two recent studies linking in utero exposure to selective serotonin reuptake inhibitors (SSRIs) with persistent pulmonary hypertension of the newborn (PPHN), a potentially serious but rare respiratory illness, have made clinicians and patients more reluctant to use SSRIs during pregnancy. However, additional clinical studies have associated maternal depression rather than SSRI exposure as a risk factor for PPHN. This review summarizes the current knowledge regarding PPHN pathophysiology, including the role of serotonin and genetic risk factors; the effects of SSRIs on pulmonary vasculature; the possible link between SSRIs and PPHN; and the diagnosis, clinical management, and prognosis of PPHN.     

The effect of selective serotonin reuptake inhibitors in healthy subjects. A systematic review

Background: Selective serotonin reuptake inhibitors (SSRIs) show antidepressant properties in many patients with a diagnosis of depression. An understanding of the underlying mechanisms of the effect of SSRIs in healthy patients may lead to an understanding of the yet unclear pathophysiology of depression. Recent reviews of studies investigating the effect of SSRIs in healthy persons conclude that the results are inconsistent and that—in relation to a wide range of outcomes—the effect of SSRIs is limited; however, reasons for the inconsistencies are poorly studied. Aims and Methods: To investigate whether methodological artefacts can explain the diverging findings, we conducted a systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of treatment by SSRI for at least a week in healthy persons published before January 2009. Results: We identified 33 trials, investigating six SSRIs and 163 outcome tests. The effect of SSRI showed divergence presumably related to methodological issues. Specifically, it is likely that the majority of studies included a mix of healthy persons with and without a family history of affective disorders. Few presented information on factors that may influence outcomes such as age, gender, family history of psychiatric disorder, drug levels and ethnicity. No study fulfilled principles of conducting and reporting randomized controlled trials, according to the CONSORT Statement guidelines. Conclusions: It is unclear whether the effect of SSRIs in healthy persons may lead to an understanding of the pathophysiology of depression, since the present evidence is divergent and may be severely influenced by a number of methodological drawbacks.     

A retrospective study of SSRI treatment in adolescent anorexia nervosa: insufficient evidence for efficacy

Although selective-serotonin-reuptake-inhibitors (SSRI) have been of limited efficacy in the treatment of eating disorder psychopathology and comorbid symptoms of malnourished patients with anorexia nervosa (AN), there is recent data suggesting that SSRI may play a role in preventing relapse among weight-restored patients. Though some previous studies included patients in late adolescence, the vast majority of investigated subjects have been adults. The aim of our retrospective study was to assess the effects of SSRI treatment in partially weight-restored children and adolescents with AN. Thirty two females with AN (mean 14.5+/-1.4 years) were investigated three times during inpatient treatment and at 3- and 6-month follow-up for BMI, eating disorder psychopathology, depressive symptomology, and obsessive-compulsive symptomology. Medication history during inpatient and outpatient treatment was reconstructed at the 6-month follow-up. Nineteen patients received SSRI treatment, while 13 subjects were non-medicated. In comparison to the non-SSRI group, the SSRI group had similar BMI and obsessive-compulsive scores, but higher levels of core eating disorder psychopathology and depressive symptoms at the start of medication. Rates of re-admissions were similar in both groups (SSRI group: 36%, non-SSRI group: 31%, Phi: p=0.72). Repeated measures ANOVA revealed no significant group with time interactions for BMI-SDS (p=0.84), core eating disorder symptoms (ANIS, p=0.79), depression (DIKJ, p=0.75), and obsessive-compulsive (CY-BOCS, p=0.40) scores indicating minimal or no effects of SSRI medication on the course of these variables. In conclusion, our results challenge the efficacy of SSRI medication in the treatment of eating disorder psychopathology as well as depressive and obsessive-compulsive comorbidity in adolescent AN. Clinicians should be chary in prescribing SSRI in adolescent AN unless randomized controlled trials have proofed the benefit of these drugs.     

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.     

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.     

On the pharmacotherapy of obsessive-compulsive disorder: is a consensus possible?

OBJECTIVE: To examine the efficacy and tolerability of clomipramine compared with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder (OCD), bearing in mind the recent Expert Consensus Guidelines recommendation to use clomipramine after 2 to 3 failed SSRI trials. METHOD: The literature on the pharmacotherapy of OCD was critically examined. RESULTS: The available research evidence is not conclusive but suggests that clomipramine possesses greater anti-obsessional efficacy than do the SSRIs. In addition, when clomipramine is presented to patients in a positive way, and properly used in small initial doses with gradual increases, it seems to be tolerated as well as the SSRIs. CONCLUSION: Recently expressed opinions that clomipramine should be used to treat OCD after 2 to 3 failed SSRI trials are not supported by research evidence. Both clomipramine and the SSRIs may be used as first-line treatments for OCD.     

Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia?

OBJECTIVE: Recently, pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available. The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines. METHOD: A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project, a prospective longitudinal study of anxiety disorders. These patients were interviewed over the course of 10 years to examine their use of psychotropic medications. RESULTS: Despite efforts aimed at increasing the use of selective serotonin reuptake inhibitors (SSRIs) in patients with panic disorder (e.g., APA's practice guideline for panic disorder, Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder), only a modest increase in their use was found. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder. In comparison, SSRI use throughout the follow-up period has remained low. Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine, nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly. CONCLUSIONS: These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed. Factors potentially associated with promoting and ignoring treatment recommendations are discussed.     

Validating the EDI-2 in three Swedish female samples: Eating disorders patients,psychiatric outpatients and normal controls

The aim of the current study was to validate the Eating Disorders Inventory 2 (EDI-2) in a Swedish population by investigating how it discriminates between three female samples aged 18 to 50 years: patients with eating disorders (n=978), psychiatric outpatients (n=106) and normal controls (n=602), as well as between different eating disorder diagnoses. The internal consistency of the EDI-2 was above 0.70 for most subscales. The EDI-2 discriminated well between patients with eating disorders and normal controls on all subscales. On the symptom-related subscales, eating disorder patients scored highest followed by psychiatric controls and normals. All subscales except Perfectionism, Interoceptive awareness and Asceticism discriminated eating disorder patients and psychiatric controls. Bulimia patients scored higher than anorexics on the symptom subscales. It is concluded that the EDI-2 discriminates well between eating disorder patients and both psychiatric and normal controls.     

Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood–brain barrier (BBB). Triozan^TM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + Triozan^TM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.     

Differential effects of perinatal exposure to antidepressants on learning and memory,acoustic startle,anxiety, and open-field activity in Sprague-Dawley rats

Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6 h apart) with 5 mg/kg CIT, 5 mg/kg FLX, 15 mg/kg BUP, or saline (SAL) from embryonic day (E) 6–21, and directly to the pups from postnatal day (P) 1–20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.     

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.