000200
10.3205/000200
urn:nbn:de:0183-0002007
Research Article
Which adverse effects influence the dropout rate in selective serotonin reuptake inhibitor (SSRI) treatment? Results for 50,824 patients
Welche unerwünschten Ereignisse haben einen Einfluss auf die Behandlungsabbruchrate von selektiven Serotonin-Wiederaufnahmehemmern (SSRI)? Ergebnis von 50.824 Patienten
Kostev
Kostev
Karel
K
Dr.
IMS Health, Darmstädter Landstraße 108, 60598 Frankfurt/Main, Germany, Phone: 0049-69-66044878IMS Health, Frankfurt, Germany
kkostev@de.imshealth.com
author
Rex
Rex
Juliana
J
IMS Health, Frankfurt, Germany
author
Eith
Eith
Thilo
T
Fresenius University of Applied Sciences, Idstein, Germany
author
Heilmaier
Heilmaier
Christina
C
FOM University of Applied Sciences, Essen, Germany
author
German Medical Science GMS Publishing House
Düsseldorf
610
antidepressants
selective serotonin reuptake inhibitors
adverse drug reactions
dropout
Antidepressiva
selektive Serotonin-Wiederaufnahmehemmer
unerwünschte Arzneimittelnebenwirkungen
Drop-Out-Rate
Behandlungsabbruch
Psychiatry
20140511
20141001
20141016
engl
1612-3174
12
GMS German Medical Science
GMS Ger Med Sci
15
Hintergrund: Heutzutage sind Serotonin-Wiederaufnahmehemmer (SSRI) aufgrund ihrer verglichen mit trizyklischen Antidepressiva oder Monoamino-Oxidase-Inhibitoren überlegenen klinischen Wirksamkeit, Verträglichkeit und Sicherheit die meistverschriebenen Antidepressiva. Dennoch sind trotz dieser Vorteile SSRIs mit einer Vielzahl an unerwünschten Arzneimittelnebenwirkungen verbunden, insbesondere im frühen Stadium der Behandlung, was in manchen Fällen zu einem verfrühtem Therapieabbruch führen kann. Das Ziel der vorliegenden Studie war es die meisten unerwünschten Arzneimittelnebenwirkungen von SSRIs zu erfassen sowie die Auswirkung auf die Behandlungsabbruchrate in einer großen Population zu ermitteln.Patienten und Methoden: Daten von 50.824 Patienten mit einer SSRI-Erstbehandlung einer schweren depressiven Störung wurden über die IMS (R) Disease Analyzer Datenbank (IMS Health) retrospektiv analysiert, wobei Informationen über unerwünschte SSRI-Nebenwirkungen und deren Einfluss auf einen verfrühten Therapieabbruch über Regressionsanalysen ermittelt wurden. Das Auftreten von bestimmten Co-Morbiditäten wurden ebenfalls registriert.Ergebnisse: Das mittlere Alter war 54.5 (±19) Jahre, zwei Drittel der Population waren weiblich. Die meist dokumentierten unerwünschten Nebenwirkungen waren: Beschwerden des Verdauungssystems (10%), Schlafstörung (8.6%) und Herzrhythmusstörung (4%); diese waren allerdings von erträglichem Ausmaß, da dadurch die Drop-Out-Rate nicht signifikant beeinflusst wurde. Hingegen erhöht insbesondere Somnolenz als Nebenwirkung und jüngeres Alter (≤50 Jahre) die Wahrscheinlichkeit eines vorzeitigen Therapieabbruchs, während Patienten mit kardiovaskulären Risikofaktoren oder Osteoporose die Tendenz aufweisen die Therapie aufrechtzuerhalten. Schlussfolgerung: Insgesamt wurde eine gute Verträglichkeit der SSRI-Behandlung nachgewiesen, wohingegen das Auftreten von Somnolenz zu einem Therapieabbruch führte.
Background: Nowadays, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants due to their superior clinical efficacy, effectiveness, tolerability, and safety as compared to tricyclic antidepressants or monoamino oxidase inhibitors. However, despite these advantages SSRIs are still associated with a number of adverse drug reactions, especially in the early stages of treatment, which may lead to premature discontinuation of therapy in some cases. The aim of the present study was to assess the most common adverse drug reactions of SSRIs as well as their impact on dropout rate in a large study population.Patients and methods: Data for 50,824 patients treated for major depressive disorder with SSRIs for the first time was accessed via the Disease Analyzer database (IMS Health, Germany), providing information on SSRI adverse drug reactions and their influence on premature treatment discontinuation calculated by regression analysis. The presence of certain co-morbidities was also registered. Results: The mean age was 54.5 ± 19 years, two-thirds of the study population being female. The adverse effects mentioned most frequently were: “discomfort” of the digestive system (10%), sleep disorders (8.6%), and heart rhythm disorders (4%); however, these were of tolerable severity as they did not significantly influence the dropout rate. Contrary to that, somnolence and younger age (≤50 years) in particular increased the chance of premature treatment discontinuation, while patients suffering from cardiovascular risk factors or osteoporosis tended to adhere to the therapy.Conclusions: Overall, there is high tolerability for early SSRI treatment, whereas the occurrence of somnolence leads to discontinuation.
IntroductionNowadays, antidepressants are one of the most frequently prescribed drugs worldwide with the class of selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) now established as the most commonly purchased since their introduction in the late 1980s , . Leading SSRIs include citalopram (Celexa®), fluoxetine (Prozac®), paroxetine (Paxil®) or sertraline (Zoloft®). They are considered mainstays in the treatment of major depressive disorder and some of them are also approved for the treatment of conditions such as panic disorder, anxiety disorder or posttraumatic stress disorder . Changes in neurotransmitter activity, such as reduced levels of serotonin or noradrenalin, may lead to the development of depression. SSRIs work by selectively blocking the presynaptic reuptake of serotonin in the brain stem and spinal cord , , thereby making more serotonin available, which in turn improves mood and behavior. In addition to their clinical efficacy and effectiveness, SSRIs have exhibited better levels of tolerability and safety than the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOs) used to date, which is probably due to their lower affinity toward other neurotransmitter systems such as α-1 adrenergic, muscarinic or histaminergic receptors or fast sodium channels that are affected by TCAs . These advantages include fewer anticholinergic effects, a better cardiovascular profile, ease of use and lower risk in case of overdose . Nevertheless, some adverse drug reactions can arise during SSRI treatment, which may ultimately lead to treatment discontinuation. These adverse effects include nausea, diarrhea, headache, insomnia, nervousness, tachycardia or weight gain, with severity varying considerably among the different SSRIs as shown in a meta-analysis published in “The Lancet” . This is due to differences in pharmacological characteristics such as variable potency of the SSRIs as inhibitors of the specific cytochrome-P450 (CYP)-enzymes , , their plasma protein binding capability or different half-lives , all influencing the likelihood of clinically significant drug-drug interactions. Sertraline and citalopram, for example, have the lowest risk of enzyme inhibition, while fluoxetine is linked with a high chance of drug interaction.The aim of the present study was to assess the most common adverse drug reactions occurring within 30 days after first prescription of SSRIs (“index date”) as well as their impact on dropout rate in a large study population of more than 50,000 patients above 18 years of age.
Patients and methodsDisease Analyzer databaseThe Disease Analyzer database (IMS HEALTH) compiles drug prescriptions, diagnoses, and basic medical and demographic data obtained directly from the computer systems from the practices of general practitioners and specialists throughout Germany . Diagnoses (ICD-10), prescriptions (Anatomical Therapeutic Chemical (ATC) Classification System), and the quality of reported data are monitored continuously by IMS on the basis of a number of quality criteria (e.g., completeness of documentation, linkage of diagnoses and prescriptions, etc.). The data are generated directly from the computers in physicians’ practices via standardized interfaces and provide daily routine information on patient diseases and therapies. Each practice transmits patient data stored on the physician’s computer to IMS on a monthly basis. Before transmission, the data are encrypted for data protection purposes. The validity of the Disease Analyzer data has already been evaluated and described , . The analysis of physicians’ age and regional distributions among participating practices showed that the selection appears to be representative of the general physician population . Further analysis indicated that the distribution of patients by health insurance fund in Disease Analyzer was very similar to the overall distribution of patients by health insurance fund in Germany . Different comparisons were also performed for diabetic medication or incidence of cancer diagnoses which were in line in statistics from Robert-Koch-Institute . It has formed the basis of a number of studies and peer-reviewed scientific publications in the fields of epidemiology and drug safety research , . Study populationFirst-time prescriptions of SSRI (ATC: N06A4) from January 2009 until December 2012 in subjects diagnosed with depression (ICD 10: F32, F33) were defined as the index dates; the latest follow-up date was identified as December 2013. Patients with a follow-up time of less than 365 days prior to the index date were excluded. This exclusion was necessary for the correct determination of treatment initiation. Age of above 18 years formed another inclusion criterion. We excluded children and adolescents from our study because they have developmentally different pharmacodynamics and pharmacokinetics compared to adults, which impacts adverse drug reactions and would distort analysis. A total of 50,824 patients were available for therapy discontinuation analysis. These patients were treated in 1,192 general practices.Study outcomesThe first outcome measure was the share of patients with defined adverse drug effects within 30 days of initial prescription of SSRI. As adverse drug reactions usually occur in first days after therapy start, the duration of <![CDATA[30 days</PlainText></TextGroup> was elected. The following adverse drug reactions were defined based on ICD 10 classification: symptoms and signs involving the digestive system and abdomen (R10–19), sleep disorders (G47), heart rhythm disorders (I45–49), dizziness (R42), malaise and fatigue (R53), headache (R51), symptoms and signs concerning food and fluid intake (R63), hyperhidrosis (R61), sexual dysfunctions (F52), gastrointestinal hemorrhage (K92.2), somnolence (R40.0) and further unspecified adverse effects (T88.7).</Pgraph><Pgraph>The impact of these adverse drug reactions on the discontinuation of SSRI treatment was also investigated. Treatment discontinuation was defined as the absence of the second SSRI prescription or a switch to another antid<TextGroup><PlainText>ep</PlainText></TextGroup>ressant class (monoamine reuptake inhibitors, monoamine oxidase inhibitors or other antidepressants).</Pgraph><SubHeadline>Covariates </SubHeadline><Pgraph>Demographic data included age, gender, health insurance status (private or statutory), and practice region (Eastern versus Western Germany). Co-diagnoses were determined based on primary care diagnoses for mental and behavioral disorders due to the use of psychoactive substances (F10–19), anxiety, dissociative, stress-related, somatoform disorders (F40–48), diabetes (E10–14), hypertension (I10), hyperlipidemia (E78), coronary heart disease (I24–25), cancer (C00–99), asthma (J45–46) and osteoporosis (M80–81).</Pgraph><Pgraph>In addition, the Charlson Comorbidity Index (CCI) was used as general marker for co-morbidity. This is a weighted index that accounts for the number and severity of comorbidities (e.g. myocardial infarction, diabetes, stroke or heart failure) in administrative database studies <TextLink reference="14"></TextLink> and helps to decide how aggressively to treat a condition. </Pgraph><SubHeadline>Statistical analysis </SubHeadline><Pgraph>A logistic regression model was used to estimate the relationship between therapy discontinuation and the adverse drug reactions. A stepwise selection procedure with the entry criterion p<0.05 was used to select the final optimal model. The adjusted odds ratios (OR) and <TextGroup><PlainText>95% c</PlainText></TextGroup>onfidence intervals (CI) are presented for the independent variables. </Pgraph><Pgraph>Potential confounders (age, gender, private health insurance, region and co-diagnoses) were included as independent variables. Two-sided tests were used and a <TextGroup><PlainText>p value</PlainText></TextGroup> of less than 0.05 was considered statistically significant. All analyses were carried out using SAS 9.3 (SAS Institute, Cary, USA). </Pgraph><Pgraph> </Pgraph></TextBlock>
<TextBlock linked="yes" name="Results">
<MainHeadline>Results</MainHeadline><SubHeadline>Patient characteristics and comorbidities</SubHeadline><Pgraph>Data from a total of 50,824 patients attending <TextGroup><PlainText>1,192 g</PlainText></TextGroup>eneral practices were available for analysis. The mean age was 54.5 ± 19 years with 45% of patients <TextGroup><PlainText>≤50 years</PlainText></TextGroup> old, two-thirds of the study population were female, 6.2% had private health insurance and 90.6% lived in the Western area of Germany (Table 1 <ImgLink imgNo="1" imgType="table"/>). Table 2 <ImgLink imgNo="2" imgType="table"/> also provides a survey on the presence of certain comorbidities with anxiety, dissociative, stress-related, and somatoform disorders (F40–48; 31.4%) or cardiovascular risk factors such as hypertension (I10; 31.7%), hyperlipidemia (E78; 14%) or diabetes (E10–14; 11%) being the most frequent. The mean Charlson Comorbidity Index (CCI) was 1.3 ± 1.0, indicating that most patients suffered from 1 or 2 comorbidities.</Pgraph><SubHeadline>Adverse drug reactions occurring during SSRI treatment</SubHeadline><Pgraph>Analysis of the adverse drug reactions arising during SSRI treatment showed that 10% of patients suffered from symptoms and signs involving the digestive system and abdomen (R10–19), 8.6% exhibited signs of sleep disorders (G47), and heart rhythm disorders occurred in 4%. Other, less frequently encountered, adverse effects are listed in Table 2 <ImgLink imgNo="2" imgType="table"/>. </Pgraph><Pgraph>Cox regression analyses revealed that somnolence was by far the most frequently cited reason for discontinuation of SSRI treatment (OR: 8.42; 95% CI: 1.86–38.10). Other factors that positively influenced the dropout rate were headache (OR: 1.32; 1.05–1.66), younger age (≤40 years) (OR: 1.19; 1.12–1.26) or male gender (OR: 1.09; 1.05–1.13), while the presence of dementia, hypertension or hyperlipidemia was associated with the continuation of SSRI treatment to a significant extent (Table 3 <ImgLink imgNo="3" imgType="table"/>) (all p<0.05).</Pgraph></TextBlock>
<TextBlock linked="yes" name="Discussion">
<MainHeadline>Discussion</MainHeadline><Pgraph>Selective serotonin reuptake inhibitors (SSRIs) are now established as the most frequently prescribed antidepressant owing to their clinical efficacy and effectiveness, high tolerability and safety <TextLink reference="2"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="8"></TextLink>. Nevertheless, adverse effects may occur during SSRI treatment, some of which may constitute a significant public health issue due to the associated poor adherence to treatment, preterm treatment discontinuation, and considerable harm incurred, as in the case of serotonin syndrome <TextLink reference="15"></TextLink> or hyponatremia <TextLink reference="6"></TextLink>, <TextLink reference="16"></TextLink>. </Pgraph><Pgraph>Accordingly, we assessed adverse effects arising during first prescription of SSRIs in a very large study group of more than 50,000 patients, providing data representative for a general adult population and not confined to a specific group (e.g. elderly patients, who inherit a known higher risk for side effects during antidepressant treatment, which may be – among other reasons – due to drug interactions <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink> or existing comorbidities <TextLink reference="20"></TextLink>). Similarly to the results presented in a report by Westenberg and Sandner <TextLink reference="8"></TextLink> we found that the most common adverse drug reactions were symptoms and signs involving the digestive system and abdomen such as nausea and diarrhea, probably due to an increased availability of 5-HT in the gastrointestinal system as well as in the brain <TextLink reference="21"></TextLink>. However, this adverse effect occurred considerably less often than described in previous literature (10% in our study versus 15–35% by Vaswani et al. <TextLink reference="2"></TextLink>) and is generally known to be transient similar as elevation of liver enzymes, which is a recognized side effect of almost all available antidepressants (especially tricyclic antidepressants (TCAs)) <TextLink reference="22"></TextLink>, <TextLink reference="23"></TextLink>. Furthermore, as others before us <TextLink reference="8"></TextLink>, we often detected sleep disorders, although evidence suggests that SSRIs generally have beneficial effects on sleep quality in persons suffering from depression <TextLink reference="24"></TextLink>. Heart rhythm disorders constituted the third most commonly encountered adverse drug reaction in our study, of which tachycardia and especially long QT syndrome and Torsade de Pointes have previously been reported on <TextLink reference="8"></TextLink>, <TextLink reference="25"></TextLink>, although a recently published study did not demonstrate a higher risk of cardiac mortality in patients taking SSRIs <TextLink reference="2"></TextLink>. Overall, it seems that these frequently observed adverse effects were of tolerable severity in our study population as regression analysis showed that they were not accompanied by considerably higher dropout rates. </Pgraph><Pgraph>Other adverse drug reactions that were often mentioned in other studies were only seldom seen in our study population, e.g. dizziness (3.6%), malaise and fatigue (3.5%), headache (3.0%), sexual dysfunction (0.5%) <TextLink reference="26"></TextLink>, <TextLink reference="27"></TextLink> or somnolence (0.1%). In particular, the low incidence of sexual disorders in our population is surprising given that other studies reported rates of more than 50% <TextLink reference="2"></TextLink>. However, as assumed by Trenque et al., our results are probably falsely low due to instances of underreporting in the case of adverse reactions that are considered too embarrassing to report spontaneously <TextLink reference="28"></TextLink>. Another explanation may be that it takes several weeks after beginning of treatment until sexual dysfunctions manifest <TextLink reference="2"></TextLink>. Furthermore, gastrointestinal hemorrhage and general bleeding risk (especially in patients that additionally have been prescribed acetylsalicylic acid <TextLink reference="29"></TextLink>), both associated with short-term use of SSRIs (7–28 days) <TextLink reference="30"></TextLink>, were only observed in a small number of patients (0.5%) within our study population. Additionally, changes in body weight, which are often associated with a low acceptance of treatment and incompliance <TextLink reference="8"></TextLink>, did not play a role in our study, which can be explained by the fact that it typically takes several months before weight changes become evident. </Pgraph><Pgraph>Although somnolence occurred only in a few persons (0.1% of our study population) it was by far the most common reason for patients to stop taking SSRI, which is probably due to the fact that patients suffering from depression are often younger (almost 45% of our study population were less than 50 years old) and are therefore still working. For the same reason, any impairment of cognitive psychomotor function or headache is often considered intolerable <TextLink reference="8"></TextLink>, although these as well as other severe adverse effects as shown in the German drug safety program in psychiatry (AMSP) <TextLink reference="22"></TextLink> are less pronounced in patients taking SSRIs than those treated with TCAs.</Pgraph><Pgraph>By contrast, the presence of dementia, osteoporosis or cardiovascular risk factors (e.g. diabetes, hypertension, hyperlipidemia) made the premature discontinuation of the drug less probable. Reasons for this may include cognitive impairment in the case of dementia or higher disease awareness in patients already suffering from cardiovascular diseases or osteoporosis, even though it was confirmed in longitudinal, cross-sectional, and prospective cohort studies that SSRIs themselves decrease bone mineral density and increase fracture risk especially in long-time users, as demonstrated by lower T-scores <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>. In addition, elderly patients may have a higher threshold for changing drugs and tend to be more likely to adhere to a doctor’s prescription due to a lower ambition for self-determination. </Pgraph><Pgraph>Our study has recognized limitations, which need to be addressed: </Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">We registered adverse drug reactions within the first 30 days after prescription only and not in the long term. This may have impacted our results negatively, given that adverse effects in antidepressants usually diminish after a while. However, the focus of our study was not on the pure occurrence of adverse drug reactions but on their severity, and on the possibility that these might lead to the premature discontinuation of drug treatment. </ListItem><ListItem level="1" levelPosition="2" numString="2.">We did not perform sub-analysis for the various members of the SSRI family, although differences exist not only with regard to the disease spectrum for which they are approved, but also regarding the nature and severity of the adverse effects they induce. This is due to serotonergic polymorphisms at the receptor and transporter level <TextLink reference="33"></TextLink> as well as their secondary binding to non-serotonergic receptors <TextLink reference="8"></TextLink>. This means that patients may respond differently to certain SSRIs (e.g. high rate of anorexia linked with fluoxetine but low rate linked with citalopram <TextLink reference="34"></TextLink>) and also explains why SSRIs are not interchangeable or why persons having discontinued intake of one SSRI because of intolerability or non-response can be treated effectively with another <TextLink reference="15"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>. </ListItem><ListItem level="1" levelPosition="3" numString="3.">Daily doses of SSRIs vary considerably, which could cause significant differences in the spectrum and severity of adverse effects experienced. In citalopram, for example, daily doses >40 mg are associated with lower risks of ventricular arrhythmia as compared to lower doses <TextLink reference="37"></TextLink>. </ListItem><ListItem level="1" levelPosition="4" numString="4.">As there is no central system that registers the drugs prescribed to a patient by different doctors, the possibility that some patients received their follow-up prescription from another doctor and were wrongly recorded as having discontinued SSRI treatment cannot be excluded. </ListItem><ListItem level="1" levelPosition="5" numString="5.">Only the presence of major depressive disorder was considered as indication for SSRI prescription, but not the severity of symptoms or suicidal ideations, which might also have influenced discontinuation of treatment. </ListItem><ListItem level="1" levelPosition="6" numString="6.">Possible confounders such as intake of over-the-counter drugs such as St. John’s Wort, which changes the pharmacokinetics of SSRIs by induction of CYP-enzymes <TextLink reference="38"></TextLink>, or the use of illicit drugs were not taken into account, although they may interact with SSRIs <TextLink reference="39"></TextLink>. </ListItem><ListItem level="1" levelPosition="7" numString="7.">Due to the short-time observation period no relevant data on the frequency of occurrence of discontinuation syndrome after long-time use of SSRIs was available <TextLink reference="40"></TextLink>, which may also be a significant healthcare problem. </ListItem><ListItem level="1" levelPosition="8" numString="8.">And finally we did not further assess the association of SSRI-use and suicide rate, although it is known that antidepressants may increase suicide rate at the beginning, while lower rates are detected in patients receiving SSRIs for a longer period of time <TextLink reference="41"></TextLink>. </ListItem></OrderedList></Pgraph><Pgraph>In summary, our study demonstrated in the context of a large study population that the most frequently encountered adverse effects occurring during the first <TextGroup><PlainText>30 days</PlainText></TextGroup> after SSRI prescription involved the digestive system, sleep or heart rhythm disorders, but were of tolerable severity. Contrary to this, somnolence or lower age were associated with premature discontinuation of therapy, while chronic illnesses such as dementia or osteoporosis were often linked with medication adherence. It will be the task of future research to account for differences in the pharmacodynamics and pharmacokinetics of the various SSRIs as well as for the “metabolic” signature of each individual person <TextLink reference="42"></TextLink> in order to contribute to personalized drug therapy, thereby improving treatment efficacy, tolerability, and compliance.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Notes">
<MainHeadline>Notes</MainHeadline><SubHeadline>Competing interests</SubHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock>
<References linked="yes">
<Reference refNo="1">
<RefAuthor>Gordon M</RefAuthor>
<RefAuthor>Melvin G</RefAuthor>
<RefTitle>Selective serotonin re-uptake inhibitors--a review of the side effects in adolescents</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Aust Fam Physician</RefJournal>
<RefPage>620-3</RefPage>
<RefTotal>Gordon M, Melvin G. Selective serotonin re-uptake inhibitors--a review of the side effects in adolescents. Aust Fam Physician. 2013 Sep;42(9):620-3.</RefTotal>
</Reference>
<Reference refNo="2">
<RefAuthor>Vaswani M</RefAuthor>
<RefAuthor>Linda FK</RefAuthor>
<RefAuthor>Ramesh S</RefAuthor>
<RefTitle>Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review</RefTitle>
<RefYear>2003</RefYear>
<RefJournal>Prog Neuropsychopharmacol Biol Psychiatry</RefJournal>
<RefPage>85-102</RefPage>
<RefTotal>Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):85-102. DOI: 10.1016/S0278-5846(02)00338-X</RefTotal>
<RefLink>http://dx.doi.org/10.1016/S0278-5846(02)00338-X</RefLink>
</Reference>
<Reference refNo="3">
<RefAuthor>Nash J</RefAuthor>
<RefAuthor>Nutt D</RefAuthor>
<RefTitle>Antidepressants</RefTitle>
<RefYear>2007</RefYear>
<RefJournal>Psychiatry</RefJournal>
<RefPage>289–94</RefPage>
<RefTotal>Nash J, Nutt D. Antidepressants. Psychiatry. 2007;(6):289–94.</RefTotal>
</Reference>
<Reference refNo="4">
<RefAuthor>Wenthur CJ</RefAuthor>
<RefAuthor>Bennett MR</RefAuthor>
<RefAuthor>Lindsley CW</RefAuthor>
<RefTitle>Classics in chemical neuroscience: fluoxetine (Prozac)</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>ACS Chem Neurosci</RefJournal>
<RefPage>14–23</RefPage>
<RefTotal>Wenthur CJ, Bennett MR, Lindsley CW. Classics in chemical neuroscience: fluoxetine (Prozac). ACS Chem Neurosci. 2014 Jan 15;5(1):14–23. DOI: 10.1021/cn400186j</RefTotal>
<RefLink>http://dx.doi.org/10.1021/cn400186j</RefLink>
</Reference>
<Reference refNo="5">
<RefAuthor>Cipriani A</RefAuthor>
<RefAuthor>Furukawa TA</RefAuthor>
<RefAuthor>Salanti G</RefAuthor>
<RefAuthor>Geddes JR</RefAuthor>
<RefAuthor>Higgins JP</RefAuthor>
<RefAuthor>Churchill R</RefAuthor>
<RefAuthor>Watanabe N</RefAuthor>
<RefAuthor>Nakagawa A</RefAuthor>
<RefAuthor>Omori IM</RefAuthor>
<RefAuthor>McGuire H</RefAuthor>
<RefAuthor>Tansella M</RefAuthor>
<RefAuthor>Barbui C</RefAuthor>
<RefTitle>Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Lancet</RefJournal>
<RefPage>746-58</RefPage>
<RefTotal>Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009 Feb 28;373(9665):746-58. DOI: 10.1016/S0140-6736(09)60046-5</RefTotal>
<RefLink>http://dx.doi.org/10.1016/S0140-6736(09)60046-5</RefLink>
</Reference>
<Reference refNo="6">
<RefAuthor>Andrade C</RefAuthor>
<RefTitle>Selective serotonin reuptake inhibitor drug interactions in patients receiving statins</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>J Clin Psychiatry</RefJournal>
<RefPage>e95-9</RefPage>
<RefTotal>Andrade C. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins. J Clin Psychiatry. 2014 Feb;75(2):e95-9. DOI: 10.4088/JCP.13f08941</RefTotal>
<RefLink>http://dx.doi.org/10.4088/JCP.13f08941</RefLink>
</Reference>
<Reference refNo="7">
<RefAuthor>Holland J</RefAuthor>
<RefAuthor>Bhogle M</RefAuthor>
<RefTitle>Sertraline and mirtazapine as geriatric antidepressants</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Psychiatr Danub</RefJournal>
<RefPage>S286-90</RefPage>
<RefTotal>Holland J, Bhogle M. Sertraline and mirtazapine as geriatric antidepressants. Psychiatr Danub. 2013 Sep;25 Suppl 2:S286-90.</RefTotal>
</Reference>
<Reference refNo="8">
<RefAuthor>Westenberg HG</RefAuthor>
<RefAuthor>Sandner C</RefAuthor>
<RefTitle>Tolerability and safety of fluvoxamine and other antidepressants</RefTitle>
<RefYear>2006</RefYear>
<RefJournal>Int J Clin Pract</RefJournal>
<RefPage>482-91</RefPage>
<RefTotal>Westenberg HG, Sandner C. Tolerability and safety of fluvoxamine and other antidepressants. Int J Clin Pract. 2006 Apr;60(4):482-91. DOI: 10.1111/j.1368-5031.2006.00865.x</RefTotal>
<RefLink>http://dx.doi.org/10.1111/j.1368-5031.2006.00865.x</RefLink>
</Reference>
<Reference refNo="9">
<RefAuthor>Becher H</RefAuthor>
<RefAuthor>Kostev K</RefAuthor>
<RefAuthor>Schröder-Bernhardi D</RefAuthor>
<RefTitle>Validity and representativeness of the “Disease Analyzer” patient database for use in pharmacoepidemiological and pharmacoeconomic studies</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Int J Clin Pharmacol Ther</RefJournal>
<RefPage>617-26</RefPage>
<RefTotal>Becher H, Kostev K, Schröder-Bernhardi D. Validity and representativeness of the “Disease Analyzer” patient database for use in pharmacoepidemiological and pharmacoeconomic studies. Int J Clin Pharmacol Ther. 2009 Oct;47(10):617-26. DOI: 10.5414/CPP47617</RefTotal>
<RefLink>http://dx.doi.org/10.5414/CPP47617</RefLink>
</Reference>
<Reference refNo="10">
<RefAuthor>Ogdie A</RefAuthor>
<RefAuthor>Langan S</RefAuthor>
<RefAuthor>Parkinson J</RefAuthor>
<RefAuthor>Dattani H</RefAuthor>
<RefAuthor>Kostev K</RefAuthor>
<RefAuthor>Gelfand JM</RefAuthor>
<RefTitle>Medical Record Databases</RefTitle>
<RefYear>2012</RefYear>
<RefBookTitle>Pharmacoepidemiology</RefBookTitle>
<RefPage>224–43</RefPage>
<RefTotal>Ogdie A, Langan S, Parkinson J, Dattani H, Kostev K, Gelfand JM. Medical Record Databases. In: Strom BL, Kimmel SE, Hennessy S, editors. Pharmacoepidemiology. 5th ed. Oxford, UK: Wiley-Blackwell; 2012. p. 224–43. DOI: 10.1002/9781119959946.ch15</RefTotal>
<RefLink>http://dx.doi.org/10.1002/9781119959946.ch15</RefLink>
</Reference>
<Reference refNo="11">
<RefAuthor>Henneicke-von Zepelin HH</RefAuthor>
<RefAuthor>Meden H</RefAuthor>
<RefAuthor>Kostev K</RefAuthor>
<RefAuthor>Schröder-Bernhardi D</RefAuthor>
<RefAuthor>Stammwitz U</RefAuthor>
<RefAuthor>Becher H</RefAuthor>
<RefTitle>Isopropanolic black cohosh extract and recurrence-free survival after breast cancer</RefTitle>
<RefYear>2007</RefYear>
<RefJournal>Int J Clin Pharmacol Ther</RefJournal>
<RefPage>143-54</RefPage>
<RefTotal>Henneicke-von Zepelin HH, Meden H, Kostev K, Schröder-Bernhardi D, Stammwitz U, Becher H. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther. 2007 Mar;45(3):143-54.</RefTotal>
</Reference>
<Reference refNo="12">
<RefAuthor>Ziller M</RefAuthor>
<RefAuthor>Ziller V</RefAuthor>
<RefAuthor>Haas G</RefAuthor>
<RefAuthor>Rex J</RefAuthor>
<RefAuthor>Kostev K</RefAuthor>
<RefTitle>Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: a patient database analysis</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Arch Gynecol Obstet</RefJournal>
<RefPage>413-9</RefPage>
<RefTotal>Ziller M, Ziller V, Haas G, Rex J, Kostev K. Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: a patient database analysis. Arch Gynecol Obstet. 2014 Feb;289(2):413-9. DOI: 10.1007/s00404-013-2983-9</RefTotal>
<RefLink>http://dx.doi.org/10.1007/s00404-013-2983-9</RefLink>
</Reference>
<Reference refNo="13">
<RefAuthor>Martin A</RefAuthor>
<RefAuthor>Young C</RefAuthor>
<RefAuthor>Leckman JF</RefAuthor>
<RefAuthor>Mukonoweshuro C</RefAuthor>
<RefAuthor>Rosenheck R</RefAuthor>
<RefAuthor>Leslie D</RefAuthor>
<RefTitle>Age effects on antidepressant-induced manic conversion</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>Arch Pediatr Adolesc Med</RefJournal>
<RefPage>773-80</RefPage>
<RefTotal>Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med. 2004 Aug;158(8):773-80. DOI: 10.1001/archpedi.158.8.773</RefTotal>
<RefLink>http://dx.doi.org/10.1001/archpedi.158.8.773</RefLink>
</Reference>
<Reference refNo="14">
<RefAuthor>Quan H</RefAuthor>
<RefAuthor>Sundararajan V</RefAuthor>
<RefAuthor>Halfon P</RefAuthor>
<RefAuthor>Fong A</RefAuthor>
<RefAuthor>Burnand B</RefAuthor>
<RefAuthor>Luthi JC</RefAuthor>
<RefAuthor>Saunders LD</RefAuthor>
<RefAuthor>Beck CA</RefAuthor>
<RefAuthor>Feasby TE</RefAuthor>
<RefAuthor>Ghali WA</RefAuthor>
<RefTitle>Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data</RefTitle>
<RefYear>2005</RefYear>
<RefJournal>Med Care</RefJournal>
<RefPage>1130-9</RefPage>
<RefTotal>Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, Saunders LD, Beck CA, Feasby TE, Ghali WA. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005 Nov;43(11):1130-9. DOI: 10.1097/01.mlr.0000182534.19832.83</RefTotal>
<RefLink>http://dx.doi.org/10.1097/01.mlr.0000182534.19832.83</RefLink>
</Reference>
<Reference refNo="15">
<RefAuthor>Garfield LD</RefAuthor>
<RefAuthor>Dixon D</RefAuthor>
<RefAuthor>Nowotny P</RefAuthor>
<RefAuthor>Lotrich FE</RefAuthor>
<RefAuthor>Pollock BG</RefAuthor>
<RefAuthor>Kristjansson SD</RefAuthor>
<RefAuthor>Doré PM</RefAuthor>
<RefAuthor>Lenze EJ</RefAuthor>
<RefTitle>Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Am J Geriatr Psychiatry</RefJournal>
<RefPage>971-9</RefPage>
<RefTotal>Garfield LD, Dixon D, Nowotny P, Lotrich FE, Pollock BG, Kristjansson SD, Doré PM, Lenze EJ. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial. Am J Geriatr Psychiatry. 2014 Oct;22(10):971-9. DOI: 10.1016/j.jagp.2013.07.003</RefTotal>
<RefLink>http://dx.doi.org/10.1016/j.jagp.2013.07.003</RefLink>
</Reference>
<Reference refNo="16">
<RefAuthor>Giorlando F</RefAuthor>
<RefAuthor>Teister J</RefAuthor>
<RefAuthor>Dodd S</RefAuthor>
<RefAuthor>Udina M</RefAuthor>
<RefAuthor>Berk M</RefAuthor>
<RefTitle>Hyponatraemia: an audit of aged psychiatry patients taking SSRIs and SNRIs</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Curr Drug Saf</RefJournal>
<RefPage>175-80</RefPage>
<RefTotal>Giorlando F, Teister J, Dodd S, Udina M, Berk M. Hyponatraemia: an audit of aged psychiatry patients taking SSRIs and SNRIs. Curr Drug Saf. 2013 Jul;8(3):175-80. DOI: 10.2174/15748863113089990036</RefTotal>
<RefLink>http://dx.doi.org/10.2174/15748863113089990036</RefLink>
</Reference>
<Reference refNo="17">
<RefAuthor>Lorgunpai SJ</RefAuthor>
<RefAuthor>Grammas M</RefAuthor>
<RefAuthor>Lee DS</RefAuthor>
<RefAuthor>McAvay G</RefAuthor>
<RefAuthor>Charpentier P</RefAuthor>
<RefAuthor>Tinetti ME</RefAuthor>
<RefTitle>Potential therapeutic competition in community-living older adults in the U.S.: use of medications that may adversely affect a coexisting condition</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>PLoS ONE</RefJournal>
<RefPage>e89447</RefPage>
<RefTotal>Lorgunpai SJ, Grammas M, Lee DS, McAvay G, Charpentier P, Tinetti ME. Potential therapeutic competition in community-living older adults in the U.S.: use of medications that may adversely affect a coexisting condition. PLoS ONE. 2014;9(2):e89447. DOI: 10.1371/journal.pone.0089447</RefTotal>
<RefLink>http://dx.doi.org/10.1371/journal.pone.0089447</RefLink>
</Reference>
<Reference refNo="18">
<RefAuthor>Schellander R</RefAuthor>
<RefAuthor>Donnerer J</RefAuthor>
<RefTitle>Antidepressants: clinically relevant drug interactions to be considered</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Pharmacology</RefJournal>
<RefPage>203-15</RefPage>
<RefTotal>Schellander R, Donnerer J. Antidepressants: clinically relevant drug interactions to be considered. Pharmacology. 2010;86(4):203-15. DOI: 10.1159/000319744</RefTotal>
<RefLink>http://dx.doi.org/10.1159/000319744</RefLink>
</Reference>
<Reference refNo="19">
<RefAuthor>Ho JM</RefAuthor>
<RefAuthor>Gomes T</RefAuthor>
<RefAuthor>Straus SE</RefAuthor>
<RefAuthor>Austin PC</RefAuthor>
<RefAuthor>Mamdani M</RefAuthor>
<RefAuthor>Juurlink DN</RefAuthor>
<RefTitle>Adverse cardiac events in older patients receiving venlafaxine: a population-based study</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>J Clin Psychiatry</RefJournal>
<RefPage>e552-8</RefPage>
<RefTotal>Ho JM, Gomes T, Straus SE, Austin PC, Mamdani M, Juurlink DN. Adverse cardiac events in older patients receiving venlafaxine: a population-based study. J Clin Psychiatry. 2014 Jun;75(6):e552-8. DOI: 10.4088/JCP.13m08508</RefTotal>
<RefLink>http://dx.doi.org/10.4088/JCP.13m08508</RefLink>
</Reference>
<Reference refNo="20">
<RefAuthor>Kemp AH</RefAuthor>
<RefAuthor>Brunoni AR</RefAuthor>
<RefAuthor>Santos IS</RefAuthor>
<RefAuthor>Nunes MA</RefAuthor>
<RefAuthor>Dantas EM</RefAuthor>
<RefAuthor>Carvalho de Figueiredo R</RefAuthor>
<RefAuthor>Pereira AC</RefAuthor>
<RefAuthor>Ribeiro AL</RefAuthor>
<RefAuthor>Mill JG</RefAuthor>
<RefAuthor>Andreão RV</RefAuthor>
<RefAuthor>Thayer JF</RefAuthor>
<RefAuthor>Benseñor IM</RefAuthor>
<RefAuthor>Lotufo PA</RefAuthor>
<RefTitle>Effects of Depression, Anxiety, Comorbidity, and Antidepressants on Resting-State Heart Rate and Its Variability: An ELSA-Brasil Cohort Baseline Study</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Am J Psychiatry</RefJournal>
<RefPage></RefPage>
<RefTotal>Kemp AH, Brunoni AR, Santos IS, Nunes MA, Dantas EM, Carvalho de Figueiredo R, Pereira AC, Ribeiro AL, Mill JG, Andreão RV, Thayer JF, Benseñor IM, Lotufo PA. Effects of Depression, Anxiety, Comorbidity, and Antidepressants on Resting-State Heart Rate and Its Variability: An ELSA-Brasil Cohort Baseline Study. Am J Psychiatry. 2014 Aug. DOI: 10.1176/appi.ajp.2014.13121605</RefTotal>
<RefLink>http://dx.doi.org/10.1176/appi.ajp.2014.13121605</RefLink>
</Reference>
<Reference refNo="21">
<RefAuthor>Meijer WE</RefAuthor>
<RefAuthor>Heerdink ER</RefAuthor>
<RefAuthor>van Eijk JT</RefAuthor>
<RefAuthor>Leufkens HG</RefAuthor>
<RefTitle>Adverse events in users of sertraline: results from an observational study in psychiatric practice in The Netherlands</RefTitle>
<RefYear>2002</RefYear>
<RefJournal>Pharmacoepidemiol Drug Saf</RefJournal>
<RefPage>655-62</RefPage>
<RefTotal>Meijer WE, Heerdink ER, van Eijk JT, Leufkens HG. Adverse events in users of sertraline: results from an observational study in psychiatric practice in The Netherlands. Pharmacoepidemiol Drug Saf. 2002 Dec;11(8):655-62. DOI: 10.1002/pds.752</RefTotal>
<RefLink>http://dx.doi.org/10.1002/pds.752</RefLink>
</Reference>
<Reference refNo="22">
<RefAuthor>Degner D</RefAuthor>
<RefAuthor>Grohmann R</RefAuthor>
<RefAuthor>Kropp S</RefAuthor>
<RefAuthor>Rüther E</RefAuthor>
<RefAuthor>Bender S</RefAuthor>
<RefAuthor>Engel RR</RefAuthor>
<RefAuthor>Schmidt LG</RefAuthor>
<RefTitle>Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>Pharmacopsychiatry</RefJournal>
<RefPage>S39-45</RefPage>
<RefTotal>Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry. 2004 Mar;37 Suppl 1:S39-45. DOI: 10.1055/s-2004-815509</RefTotal>
<RefLink>http://dx.doi.org/10.1055/s-2004-815509</RefLink>
</Reference>
<Reference refNo="23">
<RefAuthor>Wernicke J</RefAuthor>
<RefAuthor>Pangallo B</RefAuthor>
<RefAuthor>Wang F</RefAuthor>
<RefAuthor>Murray I</RefAuthor>
<RefAuthor>Henck JW</RefAuthor>
<RefAuthor>Knadler MP</RefAuthor>
<RefAuthor>D’Souza DN</RefAuthor>
<RefAuthor>Uetrecht JP</RefAuthor>
<RefTitle>Hepatic effects of duloxetine-I: non-clinical and clinical trial data</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Curr Drug Saf</RefJournal>
<RefPage>132-42</RefPage>
<RefTotal>Wernicke J, Pangallo B, Wang F, Murray I, Henck JW, Knadler MP, D’Souza DN, Uetrecht JP. Hepatic effects of duloxetine-I: non-clinical and clinical trial data. Curr Drug Saf. 2008 May;3(2):132-42. DOI: 10.2174/157488608784529189</RefTotal>
<RefLink>http://dx.doi.org/10.2174/157488608784529189</RefLink>
</Reference>
<Reference refNo="24">
<RefAuthor>Murata Y</RefAuthor>
<RefAuthor>Kamishioiri Y</RefAuthor>
<RefAuthor>Tanaka K</RefAuthor>
<RefAuthor>Sugimoto H</RefAuthor>
<RefAuthor>Sakamoto S</RefAuthor>
<RefAuthor>Kobayashi D</RefAuthor>
<RefAuthor>Mine K</RefAuthor>
<RefTitle>Severe sleepiness and excess sleep duration induced by paroxetine treatment is a beneficial pharmacological effect, not an adverse reaction</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>J Affect Disord</RefJournal>
<RefPage>1209-12</RefPage>
<RefTotal>Murata Y, Kamishioiri Y, Tanaka K, Sugimoto H, Sakamoto S, Kobayashi D, Mine K. Severe sleepiness and excess sleep duration induced by paroxetine treatment is a beneficial pharmacological effect, not an adverse reaction. J Affect Disord. 2013 Sep;150(3):1209-12. DOI: 10.1016/j.jad.2013.05.040</RefTotal>
<RefLink>http://dx.doi.org/10.1016/j.jad.2013.05.040</RefLink>
</Reference>
<Reference refNo="25">
<RefAuthor>Sarganas G</RefAuthor>
<RefAuthor>Garbe E</RefAuthor>
<RefAuthor>Klimpel A</RefAuthor>
<RefAuthor>Hering RC</RefAuthor>
<RefAuthor>Bronder E</RefAuthor>
<RefAuthor>Haverkamp W</RefAuthor>
<RefTitle>Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Europace</RefJournal>
<RefPage>101-8</RefPage>
<RefTotal>Sarganas G, Garbe E, Klimpel A, Hering RC, Bronder E, Haverkamp W. Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany. Europace. 2014 Jan;16(1):101-8. DOI: 10.1093/europace/eut214</RefTotal>
<RefLink>http://dx.doi.org/10.1093/europace/eut214</RefLink>
</Reference>
<Reference refNo="26">
<RefAuthor>Ishak WW</RefAuthor>
<RefAuthor>Christensen S</RefAuthor>
<RefAuthor>Sayer G</RefAuthor>
<RefAuthor>Ha K</RefAuthor>
<RefAuthor>Li N</RefAuthor>
<RefAuthor>Miller J</RefAuthor>
<RefAuthor>Nguyen JM</RefAuthor>
<RefAuthor>Cohen RM</RefAuthor>
<RefTitle>Sexual satisfaction and quality of life in major depressive disorder before and after treatment with citalopram in the STAR*D study</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>J Clin Psychiatry</RefJournal>
<RefPage>256-61</RefPage>
<RefTotal>Ishak WW, Christensen S, Sayer G, Ha K, Li N, Miller J, Nguyen JM, Cohen RM. Sexual satisfaction and quality of life in major depressive disorder before and after treatment with citalopram in the STAR*D study. J Clin Psychiatry. 2013 Mar;74(3):256-61. DOI: 10.4088/JCP.12m07933</RefTotal>
<RefLink>http://dx.doi.org/10.4088/JCP.12m07933</RefLink>
</Reference>
<Reference refNo="27">
<RefAuthor>Keltner NL</RefAuthor>
<RefAuthor>McAfee KM</RefAuthor>
<RefAuthor>Taylor CL</RefAuthor>
<RefTitle>Mechanisms and treatments of SSRI-induced sexual dysfunction</RefTitle>
<RefYear>2002</RefYear>
<RefJournal>Perspect Psychiatr Care</RefJournal>
<RefPage>111-6</RefPage>
<RefTotal>Keltner NL, McAfee KM, Taylor CL. Mechanisms and treatments of SSRI-induced sexual dysfunction. Perspect Psychiatr Care. 2002 Jul-Sep;38(3):111-6. DOI: 10.1111/j.1744-6163.2002.tb00665.x</RefTotal>
<RefLink>http://dx.doi.org/10.1111/j.1744-6163.2002.tb00665.x</RefLink>
</Reference>
<Reference refNo="28">
<RefAuthor>Trenque T</RefAuthor>
<RefAuthor>Maura G</RefAuthor>
<RefAuthor>Herlem E</RefAuthor>
<RefAuthor>Vallet C</RefAuthor>
<RefAuthor>Sole E</RefAuthor>
<RefAuthor>Auriche P</RefAuthor>
<RefAuthor>Drame M</RefAuthor>
<RefTitle>Reports of sexual disorders related to serotonin reuptake inhibitors in the French pharmacovigilance database: an example of underreporting</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Drug Saf</RefJournal>
<RefPage>515-9</RefPage>
<RefTotal>Trenque T, Maura G, Herlem E, Vallet C, Sole E, Auriche P, Drame M. Reports of sexual disorders related to serotonin reuptake inhibitors in the French pharmacovigilance database: an example of underreporting. Drug Saf. 2013 Jul;36(7):515-9. DOI: 10.1007/s40264-013-0069-z</RefTotal>
<RefLink>http://dx.doi.org/10.1007/s40264-013-0069-z</RefLink>
</Reference>
<Reference refNo="29">
<RefAuthor>Jeong BO</RefAuthor>
<RefAuthor>Kim SW</RefAuthor>
<RefAuthor>Kim SY</RefAuthor>
<RefAuthor>Kim JM</RefAuthor>
<RefAuthor>Shin IS</RefAuthor>
<RefAuthor>Yoon JS</RefAuthor>
<RefTitle>Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Psychosomatics</RefJournal>
<RefPage>213-20</RefPage>
<RefTotal>Jeong BO, Kim SW, Kim SY, Kim JM, Shin IS, Yoon JS. Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics. 2014 May-Jun;55(3):213-20. DOI: 10.1016/j.psym.2013.08.011</RefTotal>
<RefLink>http://dx.doi.org/10.1016/j.psym.2013.08.011</RefLink>
</Reference>
<Reference refNo="30">
<RefAuthor>Wang YP</RefAuthor>
<RefAuthor>Chen YT</RefAuthor>
<RefAuthor>Tsai CF</RefAuthor>
<RefAuthor>Li SY</RefAuthor>
<RefAuthor>Luo JC</RefAuthor>
<RefAuthor>Wang SJ</RefAuthor>
<RefAuthor>Tang CH</RefAuthor>
<RefAuthor>Liu CJ</RefAuthor>
<RefAuthor>Lin HC</RefAuthor>
<RefAuthor>Lee FY</RefAuthor>
<RefAuthor>Chang FY</RefAuthor>
<RefAuthor>Lu CL</RefAuthor>
<RefTitle>Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Am J Psychiatry</RefJournal>
<RefPage>54-61</RefPage>
<RefTotal>Wang YP, Chen YT, Tsai CF, Li SY, Luo JC, Wang SJ, Tang CH, Liu CJ, Lin HC, Lee FY, Chang FY, Lu CL. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014 Jan;171(1):54-61. DOI: 10.1176/appi.ajp.2013.12111467</RefTotal>
<RefLink>http://dx.doi.org/10.1176/appi.ajp.2013.12111467</RefLink>
</Reference>
<Reference refNo="31">
<RefAuthor>Seifert CF</RefAuthor>
<RefAuthor>Wiltrout TR</RefAuthor>
<RefTitle>Calcaneal bone mineral density in young adults prescribed selective serotonin reuptake inhibitors</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Clin Ther</RefJournal>
<RefPage>1412-7</RefPage>
<RefTotal>Seifert CF, Wiltrout TR. Calcaneal bone mineral density in young adults prescribed selective serotonin reuptake inhibitors. Clin Ther. 2013 Sep;35(9):1412-7. DOI: 10.1016/j.clinthera.2013.07.423</RefTotal>
<RefLink>http://dx.doi.org/10.1016/j.clinthera.2013.07.423</RefLink>
</Reference>
<Reference refNo="32">
<RefAuthor>Bruyère O</RefAuthor>
<RefAuthor>Reginster JY</RefAuthor>
<RefTitle>Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Endocrine</RefJournal>
<RefPage></RefPage>
<RefTotal>Bruyère O, Reginster JY. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine. 2014 Aug. DOI: 10.1007/s12020-014-0357-0</RefTotal>
<RefLink>http://dx.doi.org/10.1007/s12020-014-0357-0</RefLink>
</Reference>
<Reference refNo="33">
<RefAuthor>Staeker J</RefAuthor>
<RefAuthor>Leucht S</RefAuthor>
<RefAuthor>Laika B</RefAuthor>
<RefAuthor>Steimer W</RefAuthor>
<RefTitle>Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Genet Test Mol Biomarkers</RefJournal>
<RefPage>20-31</RefPage>
<RefTotal>Staeker J, Leucht S, Laika B, Steimer W. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomarkers. 2014 Jan;18(1):20-31. DOI: 10.1089/gtmb.2013.0217</RefTotal>
<RefLink>http://dx.doi.org/10.1089/gtmb.2013.0217</RefLink>
</Reference>
<Reference refNo="34">
<RefAuthor>Maina G</RefAuthor>
<RefAuthor>Albert U</RefAuthor>
<RefAuthor>Salvi V</RefAuthor>
<RefAuthor>Bogetto F</RefAuthor>
<RefTitle>Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>J Clin Psychiatry</RefJournal>
<RefPage>1365-71</RefPage>
<RefTotal>Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J Clin Psychiatry. 2004 Oct;65(10):1365-71. DOI: 10.4088/JCP.v65n1011</RefTotal>
<RefLink>http://dx.doi.org/10.4088/JCP.v65n1011</RefLink>
</Reference>
<Reference refNo="35">
<RefAuthor>Caccia S</RefAuthor>
<RefTitle>Metabolism of the newest antidepressants: comparisons with related predecessors</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>IDrugs</RefJournal>
<RefPage>143-50</RefPage>
<RefTotal>Caccia S. Metabolism of the newest antidepressants: comparisons with related predecessors. IDrugs. 2004 Feb;7(2):143-50.</RefTotal>
</Reference>
<Reference refNo="36">
<RefAuthor>Nurnberg HG</RefAuthor>
<RefAuthor>Thompson PM</RefAuthor>
<RefAuthor>Hensley PL</RefAuthor>
<RefTitle>Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors</RefTitle>
<RefYear>1999</RefYear>
<RefJournal>J Clin Psychiatry</RefJournal>
<RefPage>574-9</RefPage>
<RefTotal>Nurnberg HG, Thompson PM, Hensley PL. Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors. J Clin Psychiatry. 1999 Sep;60(9):574-9. DOI: 10.4088/JCP.v60n0902</RefTotal>
<RefLink>http://dx.doi.org/10.4088/JCP.v60n0902</RefLink>
</Reference>
<Reference refNo="37">
<RefAuthor>Zivin K</RefAuthor>
<RefAuthor>Pfeiffer PN</RefAuthor>
<RefAuthor>Bohnert AS</RefAuthor>
<RefAuthor>Ganoczy D</RefAuthor>
<RefAuthor>Blow FC</RefAuthor>
<RefAuthor>Nallamothu BK</RefAuthor>
<RefAuthor>Kales HC</RefAuthor>
<RefTitle>Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Am J Psychiatry</RefJournal>
<RefPage>642-50</RefPage>
<RefTotal>Zivin K, Pfeiffer PN, Bohnert AS, Ganoczy D, Blow FC, Nallamothu BK, Kales HC. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013 Jun;170(6):642-50. DOI: 10.1176/appi.ajp.2013.12030408</RefTotal>
<RefLink>http://dx.doi.org/10.1176/appi.ajp.2013.12030408</RefLink>
</Reference>
<Reference refNo="38">
<RefAuthor>Markowitz JS</RefAuthor>
<RefAuthor>Donovan JL</RefAuthor>
<RefAuthor>DeVane CL</RefAuthor>
<RefAuthor>Taylor RM</RefAuthor>
<RefAuthor>Ruan Y</RefAuthor>
<RefAuthor>Wang JS</RefAuthor>
<RefAuthor>Chavin KD</RefAuthor>
<RefTitle>Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme</RefTitle>
<RefYear>2003</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>1500-4</RefPage>
<RefTotal>Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD. Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. 2003 Sep;290(11):1500-4. DOI: 10.1001/jama.290.11.1500</RefTotal>
<RefLink>http://dx.doi.org/10.1001/jama.290.11.1500</RefLink>
</Reference>
<Reference refNo="39">
<RefAuthor>Dobry Y</RefAuthor>
<RefAuthor>Braquehais MD</RefAuthor>
<RefAuthor>Sher L</RefAuthor>
<RefTitle>Bullying, psychiatric pathology and suicidal behavior</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Int J Adolesc Med Health</RefJournal>
<RefPage>295-9</RefPage>
<RefTotal>Dobry Y, Braquehais MD, Sher L. Bullying, psychiatric pathology and suicidal behavior. Int J Adolesc Med Health. 2013;25(3):295-9. DOI: 10.1515/ijamh-2013-0065</RefTotal>
<RefLink>http://dx.doi.org/10.1515/ijamh-2013-0065</RefLink>
</Reference>
<Reference refNo="40">
<RefAuthor>Harvey BH</RefAuthor>
<RefAuthor>Slabbert FN</RefAuthor>
<RefTitle>New insights on the antidepressant discontinuation syndrome</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Hum Psychopharmacol</RefJournal>
<RefPage></RefPage>
<RefTotal>Harvey BH, Slabbert FN. New insights on the antidepressant discontinuation syndrome. Hum Psychopharmacol. 2014 Aug. DOI: 10.1002/hup.2429</RefTotal>
<RefLink>http://dx.doi.org/10.1002/hup.2429</RefLink>
</Reference>
<Reference refNo="41">
<RefAuthor>Clouston SA</RefAuthor>
<RefAuthor>Rubin MS</RefAuthor>
<RefAuthor>Colen CG</RefAuthor>
<RefAuthor>Link BG</RefAuthor>
<RefTitle>Social inequalities in suicide: the role of selective serotonin reuptake inhibitors</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Am J Epidemiol</RefJournal>
<RefPage>696-704</RefPage>
<RefTotal>Clouston SA, Rubin MS, Colen CG, Link BG. Social inequalities in suicide: the role of selective serotonin reuptake inhibitors. Am J Epidemiol. 2014 Oct;180(7):696-704. DOI: 10.1093/aje/kwu191</RefTotal>
<RefLink>http://dx.doi.org/10.1093/aje/kwu191</RefLink>
</Reference>
<Reference refNo="42">
<RefAuthor>Kaddurah-Daouk R</RefAuthor>
<RefAuthor>Weinshilboum RM</RefAuthor>
<RefAuthor> Pharmacometabolomics Research Network</RefAuthor>
<RefTitle>Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Clin Pharmacol Ther</RefJournal>
<RefPage>154-67</RefPage>
<RefTotal>Kaddurah-Daouk R, Weinshilboum RM; Pharmacometabolomics Research Network. Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther. 2014 Feb;95(2):154-67. DOI: 10.1038/clpt.2013.217</RefTotal>
<RefLink>http://dx.doi.org/10.1038/clpt.2013.217</RefLink>
</Reference>
</References>
<Media>
<Tables>
<Table format="png">
<MediaNo>1</MediaNo>
<MediaID>1</MediaID>
<Caption><Pgraph><Mark1>Table 1: Baseline characteristics of study patients</Mark1> </Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>2</MediaNo>
<MediaID>2</MediaID>
<Caption><Pgraph><Mark1>Table 2: Documented adverse drug reactions occurring during therapy with SSRIs</Mark1></Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>3</MediaNo>
<MediaID>3</MediaID>
<Caption><Pgraph><Mark1>Table 3: Cox regression analyses related association of SSRI treatment discontinuation after first prescription with defined outcomes</Mark1></Pgraph></Caption>
</Table>
<NoOfTables>3</NoOfTables>
</Tables>
<Figures>
<NoOfPictures>0</NoOfPictures>
</Figures>
<InlineFigures>
<NoOfPictures>0</NoOfPictures>
</InlineFigures>
<Attachments>
<NoOfAttachments>0</NoOfAttachments>
</Attachments>
</Media>
</OrigData>
</GmsArticle>]]></plaintext></textgroup></pgraph></textblock></origdata></gmsarticle>