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1.  Antidepressant Use and Colorectal Cancer Risk 
Pharmacoepidemiology and drug safety  2009;18(11):1111-1114.
Purpose
A previous epidemiologic study reported a 30% reduced risk of colorectal cancer among users of high doses of selective serotonin reuptake inhibitors (SSRIs). We assessed the association of colorectal cancer risk with SSRI and tricyclic antidepressant use in our hospital-based Case Control Surveillance Study.
Methods
For the SSRI analyses, we used data collected on 529 colorectal cancer cases and 1955 hospitalized controls collected from 1995 through 2008. For the tricyclic antidepressant analyses, we used data on 2889 cases and 7122 controls collected from 1976 through 2008. We used multivariable logistic regression analysis to evaluate the association of regular SSRI use and regular tricyclic antidepressant use (daily use for at least 3 continuous months) with colorectal cancer risk.
Results
The odds ratio for regular SSRI use was 0.55 (95% CI 0.35–0.88) and it did not differ by duration of use. The odds ratio was 0.47 (95% CI 0.26–0.85) for colon cancer and 0.72 (95% CI 0.37–1.41) for rectal cancer. The odds ratio for regular use of tricyclic antidepressants was 0.77 (95% CI 0.52–1.16)
Conclusions
We found an association of reduced risk of colorectal cancer with regular use of SSRIs. In light of laboratory data indicating that SSRIs may inhibit colon cancer and one previous epidemiologic study that also observed a decreased risk, further investigation of the effect of SSRIs on the risk of colorectal cancer is warranted.
doi:10.1002/pds.1808
PMCID: PMC2783290  PMID: 19623565
colorectal cancer; selective serotonin reuptake inhibitors; tricyclic antidepressants; case-control study; pharmacoepidemiology
2.  Sertraline exposure leads to small left heart syndrome in adult mice 
Pediatric research  2012;73(3):286-293.
Background
Sertraline, a selective serotonin reuptake inhibitor (SSRI), is the most commonly prescribed therapy for maternal depression. Epidemiologic studies have linked SSRI exposure with decreased fetal growth, altered autonomic regulation, and cardiac malformations. We hypothesized SSRI exposure decreases left ventricular volumes and increases adult sympathetic nervous system activation, resulting in increased adult heart rates.
Methods
C57BL/6 mice received saline or sertraline (5 or 15 mg/kg/day i.p.) on postnatal days 1–14. Adult phenotypes were assessed at 5 months.
Results
Sertraline-exposed mice had smaller left ventricular internal diameters in diastole (control 4.0 ± 0.1 mm, SSRI 3.7 ± 0.1 mm, p < 0.05), decreased stroke volumes (control 46 ± 2.6 μL, SSRI 37 ± 2.3 μL, p < 0.05), higher heart rates (control 530 ± 13 beats per minute (bpm), SSRI 567 ± 6 bpm, p <0.05) and increased urinary excretion of noradrenaline (control 174 ± 29.4 ng/mL, SSRI 276 ± 35.1 ng/mL, p<0.05). These changes were associated with increased cerebral serotonin transporter (5-HTT) expression.
Conclusion
Neonatal sertraline exposure causes long term changes in cardiac morphology and physiology. We speculate that early life SSRI exposure impairs cardiomyocyte growth and central serotonin signaling, leading to a small left heart syndrome in adult mice.
doi:10.1038/pr.2012.183
PMCID: PMC3607080  PMID: 23232669
3.  Developmental Effects of SSRI’s – Lessons learned from Animal Studies 
Selective serotonin reuptake inhibitors (SSRI’s) are utilized in the treatment of depression in pregrant and lactating women. SSRI’s 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 is a significant advantage to work 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 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.
doi:10.1016/j.ijdevneu.2007.06.003
PMCID: PMC2277509  PMID: 17706396
serotonin; neurotransmitter; CNS development
4.  Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants, Prolactin and Breast Cancer 
Frontiers in Oncology  2012;2:177.
Selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed class of antidepressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003 to 2007, and controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the Saskatchewan prescription database. Logistic regression was used to evaluate the impact of use of high and lower inhibitors of serotonin reuptake and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake were not at increased risk for breast cancer compared with non-users of SSRIs (OR = 1.01, CI = 0.88–1.17 and OR = 0.91, CI = 0.67–1.25 respectively), regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase (OR = 1.83, CI = 0.99–3.40) for long-term users of sertraline (≥24 prescriptions), given the small number of exposed cases (n = 12), the borderline statistical significance, and the wide confidence interval, these results need to be interpreted cautiously. In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.
doi:10.3389/fonc.2012.00177
PMCID: PMC3514533  PMID: 23227451
selective serotonin reuptake inhibitors; SSRIs; breast cancer; prolactin; antidepressants; case-control studies
5.  The Nordic health registers – an important source when evaluating the safety of antidepressants during pregnancy 
Clinical Epidemiology  2010;2:205-207.
Depression during pregnancy occurs frequently and selective serotonin reuptake inhibitors (SSRIs) are often the drug of choice when treating pregnant women. Most published studies found no increased risks of congenital malformations in association with SSRIs, but there are reports of various malformations for SSRIs as a group and for specific SSRIs. To assess potential adverse effects of SSRIs as one group may be questioned because of their dissimilarities and very large datasets are needed when studying specific SSRIs. The national health and population registers in the Nordic countries offer excellent opportunities to assess long term effects of exposure during fetal life. As each of the Nordic countries is small, collaborative studies including information from all the Nordic countries are warranted to fully understand risks associated with exposure to antidepressants in fetal life.
doi:10.2147/CLEP.S10426
PMCID: PMC2964074  PMID: 21042552
antidepressive agents; adverse effect; pregnancy; multicenter study
6.  Early Neurological Outcome of Young Infants Exposed to Selective Serotonin Reuptake Inhibitors during Pregnancy: Results from the Observational SMOK Study 
PLoS ONE  2013;8(5):e64654.
Background
Use of selective serotonin reuptake inhibitors (SSRI) during pregnancy is common while the effect on the infant’s neurological outcome is unknown. Our objective was to determine the effects of prenatal SSRI-exposure on the infants’ neurological functioning, adjusted for maternal mental health.
Methods
A prospective observational study from May 2007 to April 2010. The study groups comprised 63 SSRI-exposed infants (SSRI group) and 44 non-exposed infants (non-SSRI group). Maternal depression and anxiety were measured using questionnaires. The main outcome measures during the first week after birth and at three to four months were the quality of the infants’ general movements (GMs) according to Prechtl and a detailed motor optimality score. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for abnormal GM quality in the SSRI and non-SSRI groups, and adjusted for maternal depression, anxiety, and other confounders. The study was registered under 53506435 in the ISRCTN.
Findings
All infants were born around term. During the first week, abnormal GMs occurred more frequently in the SSRI group than in the non-SSRI group (59% versus 33%) and the median MOS was lower (13 versus 18). The OR for abnormal GMs in the SSRI versus the non-SSRI group was 3·0 (95% CI, 1.3 to 6.9) and increased after adjustment for confounders. At three to four months, more SSRI-exposed infants had monotonous movements (48% versus 20%) with lower median MOSs (26 versus 28). The OR for monotonous movements was 3·5 (95% CI, 1.5 to 8.6) and increased after adjusting for confounders.
Interpretation
Prenatal exposure to SSRI had an adverse effect on early neurological functioning as reflected by GM quality, irrespective of maternal depression and anxiety, and other confounders. Physicians should take this into account in consultation with parents.
doi:10.1371/journal.pone.0064654
PMCID: PMC3665535  PMID: 23785389
7.  Selective Serotonin Reuptake Inhibitors (SSRIs): Measurement of Effect on Platelet Function 
Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of out-patients with mood disorders were recruited; each was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100) concomitantly with platelet aggregation. 58 patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, p = .00001; release, p = .009); and collagen, (aggregation, p = .016; release, p = .006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but can be used to direct evaluation of bleeding in a patient taking an SSRI: Abnormal PFA-100 results suggest further evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.
doi:10.1016/j.trsl.2007.10.004
PMCID: PMC2391274  PMID: 18279816
SSRI; Platelets; PFA-100; Platelet Aggregation
8.  5-HTTLPR Genotype and Gender, but not Chronic Fluoxetine Administration, are Associated with Cortical TREK1 Protein Expression in Rhesus Macaques 
Neuroscience letters  2011;503(2):83-86.
TREK1 is a widely expressed background potassium channel. Similar to mice treated with selective serotonin reuptake inhibitors (SSRIs), TREK1 knockout mice are resistant to depression-like behavior and have elevated serotonin levels leading to speculation that TREK1 inhibition may contribute to the therapeutic effects of SSRIs. This study examined how chronic fluoxetine administration and a common functional polymorphism in the serotonin-transporter-linked promoter region (5-HTTLPR) influence cortical TREK1 expression in 24 rhesus monkeys. The short rh5-HTTLPR allele as well as female gender were associated with reduced cortical TREK1 protein expression but chronic SSRI administration had no effect. These results suggest that serotonin may influence TREK1, but that chronic SSRI treatment does not result in long lasting changes in cortical TREK1 protein expression. TREK1 gender differences may be related to gender differences in serotonin and require further research.
doi:10.1016/j.neulet.2011.08.005
PMCID: PMC3178708  PMID: 21871532
9.  Selective Serotonin Reuptake Inhibitor Antidepressant Treatment Discontinuation Syndrome: A Review of the Clinical Evidence and the Possible Mechanisms Involved 
Besides demonstrated efficacy, selective serotonin reuptake inhibitors (SSRIs) hold other advantages over earlier antidepressants such as greater tolerability and a wider range of clinical applications. However, there is a growing body of clinical evidence which suggests that SSRIs could, in some cases, be associated with a withdrawal reaction upon cessation of regular use. In addition to sensory and gastrointestinal-related symptoms, the somatic symptoms of the SSRI discontinuation syndrome include dizziness, lethargy, and sleep disturbances. Psychological symptoms have also been documented, usually developing within 1–7 days following SSRI discontinuation. The characteristics of the discontinuation syndrome have been linked to the half-life of a given SSRI, with a greater number of reports emerging from paroxetine compared to other SSRIs. However, many aspects of the neurobiology of the SSRI discontinuation syndrome (or SSRI withdrawal syndrome) remain unresolved. Following a comprehensive overview of the clinical evidence, we will discuss the underlying pathophysiology of the SSRI discontinuation syndrome and comment on the use of animal models to better understand this condition.
doi:10.3389/fphar.2013.00045
PMCID: PMC3627130  PMID: 23596418
antidepressant treatment; selective serotonin reuptake inhibitor; SSRI discontinuation syndrome; SSRI withdrawal syndrome; animal models; clinical evidence; serotonin
10.  Selective Serotonin Reuptake Inhibitors in Human Pregnancy: To Treat or Not to Treat? 
Selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed during pregnancy. The purpose of the present paper is to summarize and evaluate the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. The literature has been inconsistent. Although most studies have not shown an increase in the overall risk of major malformations, several studies have suggested that SSRIs may be associated with a small increased risk for cardiovascular malformations. Others have noted associations between SSRIs and specific types of rare major malformations. In some studies, there appears to be a small increased risk for miscarriages, which may be associated with the underlying maternal condition. Neonatal effects have been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Persistent pulmonary hypertension of the newborn has also been described with an absolute risk of <1%. The risk associated with treatment discontinuation, for example, higher frequency of relapse and increased risk of preterm delivery, should also be considered. The overall benefit of treatment seems to outweigh the potential risks.
doi:10.1155/2012/698947
PMCID: PMC3236415  PMID: 22190957
11.  Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study 
BMJ Open  2012;2(3):e001148.
Objectives
To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart.
Design
Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry.
Setting
Denmark.
Participants
Pregnant women in Denmark between 1997 and 2009 and their offspring.
Primary outcome measures
For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy.
Results
The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage.
Conclusions
The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.
Article summary
Article focus
Relationship between SSRIs and congenital malformations.
Focus on malformations of the heart.
Focus on women with paused treatment during pregnancy.
Key messages
Risks of congenital malformations of the heart are increased for infants whose mothers were exposed to an SSRI during the first trimester.
Risks of congenital malformations of the heart are not different for pregnancies exposed during the first trimester as for pregnancies with paused treatment during pregnancy.
The found risk increases are moderate in absolute terms.
Strengths and limitations of this study
Observational study—no causal relations.
Nationwide study, including all live births in the study period.
Register-based study—no recall bias.
doi:10.1136/bmjopen-2012-001148
PMCID: PMC3378942  PMID: 22710132
12.  A Pilot Study of the Pharmacodynamic Impact of SSRI Drug Selection and Beta-1 Receptor Genotype (ADRB1) on Cardiac Vital Signs in Depressed Patients: A Novel Pharmacogenetic Approach 
Psychopharmacology bulletin  2010;43(1):11-22.
Objective
The adrenergic beta-1 receptor gene (ADRB1) Ser49Gly and Arg389Gly variants differentially affect blood pressure response to beta-blocker therapy. Binding site prediction results for fluoxetine and paroxetine in a bioinformatics model, estimated that each of these particular selective serotonin reuptake inhibitors (SSRIs) have high receptor affinity as an “Adrenergic (beta) Blocker,” which was confirmed in vitro. This pilot study was conducted to understand the relationship between these “beta-blocking” SSRIs (fluoxetine and paroxetine) and cardiac vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)), when subjects are stratified by ADRB1 genotype. Previously ascertained DNA and clinical data was examined from 122 subjects recruited for a cross-sectional study of health and well being during SSRI pharmacotherapy. A multivariate linear regression analysis was used to determine which variables affected cardiac vital signs. There was a significant interaction between 389Gly variant status and “beta-blocking” SSRIs [p = 0.0353] in relation to SBP. Specifically in homozygous 389Arg subjects, those receiving “beta-blocking” SSRIs had significantly lower SBP (mean 104 mmHg) compared to the group taking other SSRIs (mean 122 mmHg) [p = 0.0437]. In these same homozygous 389Arg subjects, those receiving “beta-blocking” SSRIs also had lower HR (mean 60 bpm) compared to the other SSRIs (mean 79 bpm) [p = 0.00877]. Future prospective studies of this phenomenon are necessary to identify all genetic markers that can predict SSRI-associated cardiovascular effects that may be related to the SSRI Discontinuation Syndrome and potentially influence pharmacotherapy decisions.
PMCID: PMC3807824  PMID: 20581797
13.  Serotonin Transporter Occupancy and the Functional Neuroanatomic Effects of Citalopram in Geriatric Depression 
Objectives
The functional neuroanatomic changes associated with selective serotonin reuptake inhibitor (SSRI) treatment have been the focus of positron emission tomography (PET) studies of cerebral glucose metabolism in geriatric depression.
Design
To evaluate the underlying neurochemical mechanisms, the present study measured both cerebral glucose metabolism and serotonin transporter (SERT) availability prior to and during treatment with the SSRI, citalopram. It was hypothesized that SERT occupancy would be observed in cortical and limbic brain regions that have shown metabolic effects, as well as striatal and thalamic regions that have been implicated in prior studies in mid-life patients.
Setting
Psychiatric Outpatient Clinic.
Participants
Seven depressed patients who met DSM-IV criteria for current major depressive episode were enrolled.
Intervention
Patients underwent a twelve week open-label trial of the SSRI, citalopram.
Measurements
Patients underwent high resolution research tomography (HRRT) PET scans to measure changes in cerebral glucose metabolism and SERT occupancy by citalopram treatment (after 8–10 weeks of treatment).
Results
Three different tracer kinetic models were applied to the [11C]-DASB region of interest data and yielded similar results of an average of greater than 70% SERT occupancy in the striatum and thalamus during citalopram treatment. Voxel-wise analyses showed significant SERT occupancy in these regions, as well as cortical (e.g. anterior cingulate, superior and middle frontal, precuneus, and limbic (parahippocampal gyrus) areas that also showed reductions in glucose metabolism.
Conclusions
The findings suggest that cortical and limbic SERT occupancy may be an underlying mechanism for the regional cerebral metabolic effects of citalopram in geriatric depression.
doi:10.1097/JGP.0b013e318227f83f
PMCID: PMC3968900  PMID: 21841458
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; serotonin transporter; depression; aging
14.  Selective serotonin reuptake inhibitors in pregnancy and infant outcomes 
Paediatrics & Child Health  2011;16(9):562.
Adequate treatment of depression during pregnancy is very important for maternal, fetal and neonatal health. Selective serotonin reuptake inhibitors (SSRIs) are commonly used antidepressants. According to one American study, approximately 7% of pregnant women were prescribed an SSRI in 2004–2005. First trimester use of SSRIs, as a group, is unlikely to increase the risk of congenital malformations. Paroxetine may be associated with a small increased risk of cardiac malformations, but evidence remains inconclusive. Fetal exposure to SSRIs closer to time of birth may result in respiratory, motor, central nervous system and gastrointestinal symptoms in about 10% to 30% of newborns (SSRI neonatal behaviour syndrome). These symptoms are usually mild and transient. Persistent pulmonary hypertension of the newborn is an extremely rare consequence of fetal exposure. This information should be used to make individual risk-benefit decisions when considering the treatment of depression during pregnancy. Newborns with late-pregnancy exposure to SSRIs should be observed in hospital for at least 48 h.
PMCID: PMC3223895  PMID: 23115498
Depression in pregnancy; Neonatal abstinence; Neonatal behaviour syndrome; Selective serotonin reuptake inhibitors
15.  Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study 
BMC Surgery  2010;10:3.
Background
Selective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association.
Methods
We conducted a population-based study of the risk of re-operation due to post-surgical bleeding within two weeks of primary surgery among Danish women with primary breast cancer. Patients were categorised according to their use of SSRI: never users, current users (SSRI prescription within 30 days of initial breast cancer surgery), and former users (SSRI prescription more than 30 days before initial breast cancer surgery). We calculated the risk of re-operation due to post-surgical bleeding within 14 days of initial surgery, and the relative risk (RR) of re-operation comparing SSRI users with never users of SSRI adjusting for potential confounders.
Results
389 of 14,464 women (2.7%) were re-operated. 1592 (11%) had a history of SSRI use. Risk of re-operation was 2.6% among never users, 7.0% among current SSRI users, and 2.7% among former users. Current users thus had an increased risk of re-operation due to post-operative bleeding (adjusted relative risk = 2.3; 95% confidence interval (CI) = 1.4, 3.9) compared with never users. There was no increased risk of re-operation associated with former use of SSRI (RR = 0.93, 95% CI = 0.66, 1.3).
Conclusions
Current use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer.
doi:10.1186/1471-2482-10-3
PMCID: PMC2823600  PMID: 20096133
16.  The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain 
OBJECTIVE
To assess the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the management of chronic pain.
METHODS
Randomized, controlled trials of SSRIs in the management of chronic pain were identified by searching MEDLINE from 1966 to 1997 and by contacting the manufacturers of SSRIs available in the United States.
MAIN RESULTS
Nineteen studies were identified, including 10 on the treatment of headache, 3 on diabetic neuropathy, 3 on fibromyalgia, and 3 on mixed-chronic pain. SSRIs were consistently helpful for mixed-chronic pain. Results were conflicting for migraine headache, tension headache, diabetic neuropathy, and fibromyalgia.
CONCLUSIONS
SSRIs appear to be beneficial for mixed-chronic pain. It is unclear, from the available evidence, whether SSRIs are beneficial for migraine headaches, tension headaches, diabetic neuropathy, or fibromyalgia. For those patients it may be reasonable to reserve SSRIs for those who fail to respond to other medications or who are intolerant of their side effects.
doi:10.1046/j.1525-1497.1997.00064.x
PMCID: PMC1497123  PMID: 9192257
chronic pain; management of; selective serotonin reuptake inhibitors
17.  Antidepressant use in children and adolescents: Practice touch points to guide paediatricians 
Paediatrics & Child Health  2011;16(9):549-553.
Depression in children and youth is common, and requires an understanding of its developmental character and associated comorbid conditions. Initial treatment of mild depression involves active supportive measures with a focus on symptom reduction and improved daily function. Where pharmacotherapy is warranted, evidence supports the use of selective serotonin reuptake inhibitor (SSRI) antidepressants, particularly fluoxetine, to manage moderate/severe depression. SSRI treatment should include a comprehensive management plan in the context of interdisciplinary care, an understanding of its pharmacology and clearly articulated goals for symptom reduction, functional status tracking (school, home and peers) and monitoring for the emergence of suicidal ideation/behaviour. For children with more severe symptoms or complicating factors (comorbid conditions), referral to mental health clinicians should be considered. Use of an SSRI should be associated with family/patient education about medication effects, specific social and health goals that promote self-esteem, improved function and close monitoring for adverse effects.
PMCID: PMC3223889  PMID: 23115493
Depression in children and youth; Management of depression in a paediatric community setting; Selective serotonin reuptake inhibitor (SSRI) antidepressants
18.  Tolerability and safety of fluvoxamine and other antidepressants 
Summary
Selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) and the 5-HT noradrenaline reuptake inhibitor, venlafaxine, are mainstays in treatment for depression. The highly specific actions of SSRIs of enhancing serotonergic neurotransmission appears to explain their benefit, while lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile compared with tricyclic antidepressants. Although SSRIs (and venlafaxine) have similar adverse effects, certain differences are emerging. Fluvoxamine may have fewer effects on sexual dysfunction and sleep pattern. SSRIs have a cardiovascular safety profile superior to that of tricyclic antidepressants for patients with cardiovascular disease; fluvoxamine is safe in patients with cardiovascular disease and in the elderly. A discontinuation syndrome may develop upon abrupt SSRI cessation. SSRIs are more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide. Although the literature suggests that there are no clinically significant differences in efficacy amongst SSRIs, treatment decisions need to be based on considerations such as patient acceptability, response history and toxicity.
doi:10.1111/j.1368-5031.2006.00865.x
PMCID: PMC1448696  PMID: 16620364
Antidepressants; selective serotonin reuptake inhibitors; fluvoxamine; tolerability; safety; review
19.  Change in Cognitive Functioning Following Acute Antidepressant Treatment in Late-Life Depression 
Objective
Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly prescribed medications for geriatric depression. The association of late-life depression and cognitive impairment has been well documented. However, there have been few placebo-controlled trials examining the impact of SSRIs on cognitive functioning.
Design
Pre-post neuropsychological data collected as part of an 8-week, double-blind, placebo-controlled trial of citalopram in depressed patients aged 75 years and older were used to examine change in cognitive functioning.
Setting
University affiliated outpatient psychiatry clinics.
Participants
One hundred seventy-four community dwelling men and women 75 years or older with non-psychotic unipolar depression.
Measurements
Neuropsychological assessments included mental status (Mini-Mental Status Exam), psychomotor speed (WAIS-III Digit Symbol Subtest), reaction time (Choice Reaction Time), visual-spatial skill (Judgment of Line Orientation), executive functioning (Stroop Color/Word Test), and memory (Buschke Selective Reminding Test).
Results
Differences in the pattern of change by treatment group depended on responder status. Citalopram non-responders were the only group to decline on verbal learning and psychomotor speed. Citalopram responders showed significant improvement in visuospatial functioning compared to non-responders in either condition, but their improvement was not greater than responders on placebo. Citalopram responders showed greater improvement on psychomotor speed than citalopram non-responders, but their improvement was not greater than placebo responders or non-responders.
Conclusions
Medication may have a deleterious effect on some aspects of cognition among patients age 75 and over who have not responded. This suggests that patients should not be maintained on a medication if they have not had an adequate response.
PMCID: PMC3852681  PMID: 19916207
cognitive functioning; cognitive impairment; geriatric depression; late-life depression; citalopram
20.  Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure 
Current Neuropharmacology  2008;6(4):293-310.
The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.
doi:10.2174/157015908787386104
PMCID: PMC2701282  PMID: 19587851
Fluoxetine; sertraline; paroxetine; fluvoxamine; citalopram; escitalopram; intraocular pressure; side effects.
21.  Congenital Heart Disease Associated With Selective Serotonin Reuptake Inhibitor Use During Pregnancy 
Mayo Clinic Proceedings  2009;84(1):23-27.
OBJECTIVE: To determine the risk of congenital cardiac abnormalities associated with use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy.
PATIENTS AND METHODS: We conducted a retrospective review of the medical records of all pregnant women presenting at Mayo Clinic's site in Rochester, MN, from January 1, 1993, to July 15, 2005, and identified 25,214 deliveries. A total of 808 mothers were treated with SSRIs at some point during their pregnancy. We reviewed the medical records of the newborns exposed to SSRIs during pregnancy to analyze their outcomes, specifically for congenital heart disease and persistent pulmonary hypertension of the newborn.
RESULTS: Of the study patients, 808 (3.2%) took an SSRI at some point during the antenatal period. Of the 25,214 deliveries, 208 newborns (0.8%) were diagnosed as having congenital heart disease. Of the 808 women exposed to SSRI during pregnancy, 3 (0.4%) had congenital heart disease compared with 205 (0.8%) of the 24,406 women not exposed to an SSRI (P=.23). Of the total number of deliveries, 16 newborns were diagnosed as having persistent pulmonary hypertension of the newborn, none of whom had exposure to SSRIs (P>.99).
CONCLUSION: Our data are reassuring regarding the safety of using SSRIs during pregnancy.
Of the 808 women who took a selective serotonin reuptake inhibitor during pregnancy, 3 (0.4%) had congenital heart disease; of the 25,214 deliveries, 208 newborns (0.8%) were diagnosed as having congenital heart disease; these findings reconfirm the safety of these drugs for pregnant women.
PMCID: PMC2664566  PMID: 19121250
22.  5-HT2B receptors are required for serotonin-selective antidepressant actions 
Molecular Psychiatry  2011;17(2):154-163.
The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacologic inactivation of 5-HT2B receptors. Conversely, direct agonist stimulation of 5-HT2B receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT2B receptors, and (iii) a selective 5-HT2B agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT2B receptors. The 5-HT2B receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT2B receptor should be considered as a new tractable target in the combat against depression.
doi:10.1038/mp.2011.159
PMCID: PMC3381222  PMID: 22158014
8-Hydroxy-2-(di-n-propylamino)tetralin; adverse effects; Analysis of Variance; Animals; Bromodeoxyuridine; metabolism; Cell Differentiation; drug effects; Chromatography, High Pressure Liquid; Exploratory Behavior; Fluoxetine; pharmacology; Gene Expression Regulation; Hippocampus; Hypothermia; chemically induced; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Neurogenesis; Reaction Time; Receptor, Serotonin, 5-HT2B; deficiency; physiology; Serotonin; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; adverse effects; Serotonin Uptake Inhibitors; Time Factors; Transcription Factors; serotonin levels; 5-HT2B receptors; antidepressants; neurogenesis
23.  Treatment-emergent mania/hypomania in unipolar patients 
Bipolar Disorders  2008;10(6):726-732.
Objective
The aim of this study was to estimate the incidence of treatment-emergent mania/hypomania (TEMH) and to describe the clinical characteristics of patients with major depression experiencing this event during treatment with a selective serotonin reuptake inhibitor (SSRI) and/or interpersonal psychotherapy (IPT).
Methods
Following an algorithm-based protocol, 344 patients with major depression confirmed with the Structured Clinical Interview for DSM-IV disorders were treated with an SSRI, interpersonal psychotherapy, or their combination for nine months. The emergence of mania/hypomania was carefully monitored throughout the study using the Young Mania Rating Scale and clinical assessment.
Results
Overall, eight patients experienced TEMH. The incidence of this event was 3.0% in patients treated with an SSRI and 0.9% in patients treated with IPT alone. Among patients treated with an SSRI, the difference between sites was higher than expected by chance alone (6.8% at Pisa and 0% at Pittsburgh, p = 0.002). Despite the adoption of an identical protocol at the two sites, some demographic and clinical characteristics of participants may account for this unexpected result. Alternatively, the greater number of episodes and earlier age of onset at the Pittsburgh site suggests that the unipolar course of illness was more clearly established prior to study entry.
Conclusions
TEMH is an infrequent event, occurring in 2.3% of patients treated for major depression. Nevertheless, its consequences are clinically relevant and require prompt and appropriate therapeutic interventions. For this reason, recognising those patients at risk for such an event is of paramount clinical significance. The observed difference in the incidence of TEMH between the two sites requires further investigation.
doi:10.1111/j.1399-5618.2008.00613.x
PMCID: PMC3387568  PMID: 18837867
bipolar; hypomania; mania; treatment; unipolar
24.  Can selective serotonin inhibitor drugs in elderly patients in nursing homes be reduced? 
Objective
To investigate whether treatment with selective serotonin reuptake inhibitors (SSRIs) could be withdrawn for elderly residents who had been on treatment for at least one year and to evaluate a method for systematic drug review.
Design
Open, prospective, interventional study.
Setting
Four counties in Sweden.
Subjects
Elderly residents at 19 nursing homes, with ongoing treatment with SSRIs for more than one year.
Main outcome measures
Clinical evaluation, registration of drugs used and rating with Montgomery–Åsberg Depression Rating Scale (MADRS). A semi-structured telephone interview with 15 participating physicians and 19 nurses.
Results
About one-third of all 822 residents in the nursing homes had ongoing antidepressant treatment, predominantly with SSRIs; 75% of them had been treated with SSRIs for at least one year and 119 (60%) of these were considered eligible for the study. The intervention was judged successful in 52% of these residents of whom 88% had a MADRS rating of less than 20 points. The GPs and the nurses experienced the method as practicable.
Conclusions
Withdrawal of SSRI treatment was successful in the majority of cases. The MADRS may be a valuable addition to clinical evaluation when deciding whether to end or continue SSRI treatment.
doi:10.1080/02813430600958427
PMCID: PMC3389450  PMID: 17354152
Family practice; nursing homes; SSRI drugs; systematic drug review; withdrawal
25.  Effect of a single dose of citalopram on amygdala response to emotional faces 
The British Journal of Psychiatry  2009;194(6):535-540.
Background
Selective serotonin reuptake inhibitors (SSRIs) are typically thought to have a delay of several weeks in the onset of their clinical effects. However, recent reports suggest they may have a much earlier therapeutic onset. A reduction in amygdala responsivity has been implicated in the therapeutic action of SSRIs.
Aims
To investigate the effect of a single dose of an SSRI on the amygdala response to emotional faces.
Method
Twenty-six healthy volunteers were randomised to receive a single oral dose of citalopram (20 mg) or placebo. Effects on the processing of facial expressions were assessed 3 h later using functional magnetic resonance imaging.
Results
Volunteers treated with citalopram displayed a significantly reduced amygdala response to fearful facial expressions compared with placebo.
Conclusions
Such an immediate effect of an SSRI on amygdala responses to threat supports the idea that antidepressants have an earlier onset of therapeutically relevant effects than conventionally thought.
doi:10.1192/bjp.bp.108.056093
PMCID: PMC2802527  PMID: 19478294

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