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1.  Citalopram--a review of pharmacological and clinical effects. 
OBJECTIVE: To provide clinicians with a critical evaluation of citalopram, a selective serotonin reuptake inhibitor (SSRI) that has been available in Canada since March 1999. DATA SOURCES: Commercial searches (MEDLINE and BiblioTech) and an "in-house" search (InfoDrug) were used to find published English-language references for clinical and preclinical publications. There was no restriction of publication dates. Primary index terms used were: pharmacological properties, receptors, pharmacological selectivity, pharmacokinetics, age-related pharmacokinetics, sex-related pharmacokinetics, renal dysfunction, hepatic dysfunction, cytochrome activity, drug interactions, adverse reactions, antidepressant switching, precautions, overdose, drug discontinuation, children, geriatric, depression, combination therapy, placebo control, refractory depression, anxiety disorders and medical disorders. STUDY SELECTION: A total of 74 studies were reviewed. Twenty-one of these studies specifically examined the clinical efficacy and tolerability of citalopram in depressive disorders as well as other disorders. In depressive disorders, clinical studies were required to have either placebo or active comparison controls for a minimum of 3 weeks. For other disorders, in the absence of double-blind trials, open-label studies were included. Pharmacological studies were limited to animal studies focusing on citalopram's selectivity and receptor specificity, and positron emission tomography studies were incorporated to include human pharmacological data. Pharmacokinetic studies focused on the metabolism, safety and tolerability of citalopram, specifically with reference to adverse reactions, drug interactions and overdose in addition to citalopram's effect on vulnerable populations, such as children, the elderly and patients with metabolic diseases. DATA EXTRACTION: Data on clinical studies were summarized according to test measures, study duration and outcome of study. Pharmacokinetic and pharmacodynamic studies were summarized according to properties and interactions. Adverse reactions were extracted to outline citalopram's safety profile. DATA SYNTHESIS: Citalopram is an SSRI antidepressant with a more specific and selective pharmacological profile than other antidepressants of its class. It is well tolerated, and drug interactions are not a significant concern. It is also reasonably safe for populations vulnerable to pharmacokinetic effects, such as the elderly and patients with metabolic diseases. In addition to its tolerability, citalopram is effective in the treatment of major depression, other depressive disorders and panic disorder. It has the potential to effectively treat other anxiety disorders and substance-use disorders; in addition, it may be useful in several medical conditions. CONCLUSIONS: There is evidence to support the role of citalopram as a well-tolerated and effective SSRI antidepressant. There is a need for further evaluation of its role in psychiatric disorders other than major depressive disorder.
PMCID: PMC1407724  PMID: 10863884
2.  Treatment of subsyndromal depressive symptoms in middle-aged and older adults with schizophrenia: effect on functioning 
Background
Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. SSRI’s appear to be helpful in alleviating depressive symptoms in patients with schizophrenia who have SSD in patients age 40 and greater. It is not known whether SSRI’s help improve functioning in this population. We hypothesized that treating this population with the SSRI citalopram would lead to improvements in social, mental and physical functioning as well as improvements in medication management and quality of life.
Methods
Participants were 198 adults ≥ 40 years old with schizophrenia or schizoaffective disorder who met study criteria for subsyndromal depression based on having two or more of the nine DSM-IV symptoms of a major depressive episode, for at least 2 weeks, and a Hamilton depression rating scale (HAM-D 17) score ≥ 8. Patients were randomly assigned to flexible-dose treatment with citalopram or placebo augmentation of their current antipsychotic medication(s) which was stable for 1 month. Subjects were assessed with the following functional scales at baseline and at the end of the 12-week trial: (1) social skills performance assessment (SSPA), (2) medication management ability assessment (MMAA), (3) mental and physical components of the medical outcomes study SF-12 Scale, and (4) the Heinrichs quality of life scale (QOLS). Analysis of covariance (ANCOVA) was used to compare differences between endpoint scores of the citalopram and placebo treated groups, controlling for site and baseline scores. ANCOVAs were also used to compare differences in the above endpoint scores in responders versus non-responders (responders = those with > 50% reduction in depressive symptoms).
Results
Overall, the citalopram group had significantly higher SSPA, mental functioning SF-12, and quality of life scale (QOLS) scores compared to the placebo group. There was no effect on MMAA or physical functioning SF-12 scores. Responders had significantly better endpoint mental SF-12 and QOLS scores compared to non-responders. Response to citalopram in terms of depressive symptoms mediated the effect of citalopram on mental functioning, but not on the quality of life.
Conclusions
Citalopram augmentation of antipsychotic treatment in middle aged and older patients with schizophrenia and subsyndromal depression appears to improve social and mental health functioning as well as quality of life. Thus it is important for clinicians to monitor these aspects of functioning when treating this population of patients with schizophrenia with SSRI agents.
doi:10.1002/gps.2318
PMCID: PMC3073368  PMID: 19711335
schizophrenia; citalopram; depression; functioning; social skills
3.  Citalopram for major depressive disorder in adults: a systematic review and meta-analysis of published placebo-controlled trials 
BMJ Open  2011;1(2):e000106.
Objective
To assess the effectiveness of citalopram for major depressive disorder (MDD) in adults, in a systematic review of all published, randomised, double-blind studies comparing it with a placebo.
Data sources
Cochrane Central Register of Controlled Trials, Medline, PsychINFO and Embase.
Study selection
Randomised, double-blind, placebo-controlled studies of citalopram in adults with MDD were included. Studies with medically ill or treatment resistant subjects were excluded, as were studies of relapse prevention. Remission of MDD was defined as a primary outcome, and response or change from baseline scores were defined as secondary.
Data extraction
Remission, response and symptom improvement scores on the Hamilton Depression Scale, Montgomery–Asberg Depression Rating Scale and Clinical Global Impressions-Severity scales were extracted. A random-effects meta-analysis was carried out on the response rates and symptom improvement scores. Included studies were examined for the presence of bias and small study effects.
Results
Eight studies (n=2025) met the inclusion criteria. Two studies provided data on remission, but only one of these showed a significant difference between citalopram and placebo (RR=1.59, 95% CI 1.10 to 2.31). Meta-analysis of response rates in five studies (n=1010) revealed significant superiority of citalopram (RR=1.42, 95% CI 1.17 to 1.73). Meta-analysis of change from baseline scores in five studies (n=1541) gave a standardised mean difference (Hedges' g) of −0.27 (95% CI −0.38 to to −0.16), showing a reduction in MDD symptoms to be significant for citalopram relative to placebo. There was no evidence of any significant small study effects. The overall quality of reporting was poor, with insufficient information on the methodology or outcomes. Seven studies received industry sponsorship.
Conclusions
Data concerning remission rates for citalopram, relative to placebo, are inconclusive. Response rates and symptom reduction scores in citalopram-treated patients with MDD are significantly better relative to placebo treatment, according to a meta-analysis of published reports. Evaluation of unpublished data is necessary to assess more definitively the effectiveness of citalopram for MDD.
Article summary
Article focus
Systematic review and meta-analysis of published randomised double-blind studies comparing citalopram with placebo in adults with major depressive disorder (MDD).
Evaluation of the quality of published studies and the risk of bias.
Key messages
Data on remission rates for citalopram in MDD, relative to placebo, are inconclusive
Response rates and symptom improvement scores are significantly better in citalopram-treated patients than in those taking placebo.
The quality of reporting in published studies is poor.
Further evaluation of citalopram is necessary, incorporating unpublished research.
Strengths and limitations of this study
This review is based on a thorough search for published placebo-controlled studies of citalopram for adults with MDD, using a broad search strategy. In a departure from previously published reviews, this study assesses the risk of bias and includes remission as a primary outcome.
This study would have been enhanced if the missing data were available for a more complete analysis, and unpublished studies satisfying inclusion criteria were incorporated into this review.
This review was carried out by a single author.
doi:10.1136/bmjopen-2011-000106
PMCID: PMC3191585  PMID: 22021869
4.  Cost-effectiveness evaluation of escitalopram in major depressive disorder in Italy 
Background
Depression has a lifetime prevalence of 10%–25% among women and 5%–12% among men. Selective serotonin reuptake inhibitors (SSRIs) are the most used and the most cost-effective treatment for long-term major depressive disorder. Since the introduction of generic SSRIs, the costs of branded drugs have been questioned. The objective of this study was to assess the cost-effectiveness (€ per quality-adjusted life year [QALY]) of escitalopram (which is still covered by a patent) compared with paroxetine, sertraline, and citalopram, the patents for which have expired.
Methods
A decision analytic model was adapted from the Swedish Dental and Pharmaceutical benefits agency model to reflect current clinical practice in the treatment of depression in Italy in collaboration with an expert panel of Italian psychiatrists and health economists. The population comprised patients with a first diagnosis of major depressive disorder and receiving for the first time one of the following SSRIs: escitalopram, sertraline, paroxetine, and citalopram. The time frame used was 12 months. Efficacy and utility data for the original model were validated by our expert panel. Local data were considered for resource utilization and for treatment costs based on the Lombardy region health service perspective. Several scenario simulations, oneway sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model.
Results
The base case scenario showed that escitalopram had an incremental cost-effectiveness ratio (ICER) of €4395 and €1080 per QALY compared with sertraline and paroxetine, respectively. Escitalopram was dominant over citalopram, which was confirmed by most one-way sensitivity analyses. The escitalopram strategy gained 0.011 QALYs more than citalopram, 0.008 more than paroxetine, and around 0.007 more than sertraline. Monte Carlo simulations indicated that ICER values for escitalopram were centered around €1100 and €4400 per QALY compared with paroxetine and sertraline, respectively. Although there is no official cost-effectiveness threshold in Italy, the value of €25,000 per QALY could be acceptable. All ICER values retrieved in all analyses were lower than this threshold.
Conclusion
The findings from this cost-effectiveness analysis indicate that escitalopram could be accepted as a cost-effective strategy for the Lombardy region health service compared with the other SSRIs studied. The present assessment is based on ICER values resulting from this analysis, which are lower than the thresholds proposed by health care authorities in other European Union countries. These benefits are driven by the effectiveness of escitalopram, which result in an improved health-related quality of life, a higher probability of sustained remission, and better utilization of health care resources. The study results are robust and in line with other pharmacoeconomic analyses comparing escitalopram with other SSRIs.
doi:10.2147/CEOR.S39492
PMCID: PMC3570079  PMID: 23413176
CEA; depression; escitalopram; Lombardy; ICER; SSRI
5.  Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study 
Journal of Women's Health  2013;22(2):121-131.
Abstract
Background
Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.
Methods
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score.
Results
Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.
Conclusions
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
doi:10.1089/jwh.2012.3479
PMCID: PMC3613168  PMID: 23398127
6.  Citalopram versus other anti-depressive agents for depression 
Background
Recent US and UK clinical practice guidelines recommend that second-generation antidepressants should be considered amongst the best first-line options when drug therapy is indicated for a depressive episode. Systematic reviews have already highlighted some differences in efficacy between second-generation antidepressants. Citalopram, one of the first selective serotonin reuptake inhibitors (SSRI) introduced in the market, is one of these antidepressant drugs that clinicians use for routine depression care.
Objectives
To assess the evidence for the efficacy, acceptability and tolerability of citalopram in comparison with tricyclics, heterocyclics, other SSRIs and other conventional and non-conventional antidepressants in the acute-phase treatment of major depression.
Search methods
We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to February 2012. No language restriction was applied. We contacted pharmaceutical companies and experts in this field for supplemental data.
Selection criteria
Randomised controlled trials allocating patients with major depression to citalopram versus any other antidepressants.
Data collection and analysis
Two reviewers independently extracted data. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (the number of patients who responded or remitted), patient acceptability (the number of patients who failed to complete the study) and tolerability (side-effects).
Main results
Thirty-seven trials compared citalopram with other antidepressants (such as tricyclics, heterocyclics, SSRIs and other antidepressants, either conventional ones, such as mirtazapine, venlafaxine and reboxetine, or non-conventional, like hypericum). Citalopram was shown to be significantly less effective than escitalopram in achieving acute response (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.08 to 2.02), but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96) and reboxetine (OR 0.63, 95% CI 0.43 to 0.91). Significantly fewer patients allocated to citalopram withdrew from trials due to adverse events compared with patients allocated to tricyclics (OR 0.54, 95% CI 0.38 to 0.78) and fewer patients allocated to citalopram reported at least one side effect than reboxetine or venlafaxine (OR 0.64, 95% CI 0.42 to 0.97 and OR 0.46, 95% CI 0.24 to 0.88, respectively).
Authors’ conclusions
Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy, tolerability and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less efficacious than escitalopram. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.
doi:10.1002/14651858.CD006534.pub2
PMCID: PMC4204633  PMID: 22786497
Antidepressive Agents [*therapeutic use]; Antidepressive Agents, Second-Generation [therapeutic use]; Citalopram [*therapeutic use]; Cyclohexanols [therapeutic use]; Depression [*drug therapy]; Morpholines [therapeutic use]; Paroxetine [therapeutic use]; Serotonin Uptake Inhibitors [therapeutic use]; Humans
7.  GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol 
Trials  2008;9:29.
Background
The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors – SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors – NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics.
Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the 5HT transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs.
Methods/design
The GenPod trial is a multi-centre randomised controlled trial. GPs referred patients aged between 18–74 years presenting with a new episode of depression, who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse. Patients were interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score > 14) were randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. The final number randomised to the trial was 601. Follow-up assessments took place at 2, 6 and 12 weeks following randomisation. Primary outcome was measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments.
Discussion
The results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression.
The trial is expected to report in the autumn of 2008.
Trial Registration
ISRCTN 31345163
doi:10.1186/1745-6215-9-29
PMCID: PMC2426669  PMID: 18498636
8.  Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease 
Brain  2014;137(4):1145-1155.
Impulsivity is common in Parkinson’s disease. In a double-blind, placebo-controlled study with multi-modal imaging, Ye et al. reveal improved response inhibition in some patients receiving the SSRI citalopram, including those with advanced disease. Improvements correlated with preserved frontostriatal structural connectivity and drug-induced prefrontal activity, highlighting the need for patient stratification in trials.
Impulsivity is common in Parkinson’s disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic ‘overdose’ and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson’s disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46–76 years old, 11 male, Hoehn and Yahr stage 1.5–3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54–74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson’s disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson’s Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson’s disease.
doi:10.1093/brain/awu032
PMCID: PMC3959561  PMID: 24578545
Parkinson’s disease; response inhibition; serotonin; citalopram; functional MRI
9.  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
10.  SEROTONIN MODULATION OF CEREBRAL GLUCOSE METABOLISM: SEX AND AGE EFFECTS 
Synapse (New York, N.Y.)  2012;66(11):955-964.
The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20–79 years) underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response.
doi:10.1002/syn.21590
PMCID: PMC3440524  PMID: 22836227
selective serotonin reuptake inhibitors; citalopram; serotonin; positron emission tomography (PET); glucose metabolism; sex differences; aging
11.  Modeling of the Temporal Patterns of Fluoxetine Prescriptions and Suicide Rates in the United States 
PLoS Medicine  2006;3(6):e190.
Background
To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960–2002.
Methods and Findings
Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (rs = −0.92; p < 0.001). Mathematical modeling of what suicide rates would have been during the 1988–2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400–45,000).
Conclusions
The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988–2002.
An association has been shown between the introduction of the antidepressant fluoxetine in the USA in 1988 and a reduction in the number of suicides.
Editors' Summary
Background.
Depression is very common. For example, in the US, an estimated 10% of men and 20% of women will suffer from major depression at some stage in their lives. One way of treating the condition is with drugs. Several types of antidepressant drugs are available, and in many countries they are among the most commonly prescribed medicines. However, all antidepressants have side effects.
One family of antidepressants, called selective serotonin uptake inhibitors (SSRIs), was introduced in the late 1980s. The name of these drugs comes from their effect, which is to prevent the removal (reuptake) from the nerve endings of one type of chemical (serotonin) that is important for transmitting nerve impulses between brain cells. SSRIs are claimed to be more effective and to have fewer side effects than older antidepressants, and many brands of SSRI are now on the market. However, in recent years there have been claims that some people taking SSRIs have committed suicide as a result of the drugs. Whether the SSRIs are the cause of the suicide is hard to know, because people who are depressed do sometimes feel like killing themselves; so if a depressed person taking an SSRI commits suicide, it is hard to tell whether this is a result of the depression or a side effect of the treatment (the SSRI). The drug regulatory authorities in some countries are now carefully studying the issue of suicides and antidepressant use, both in adults and in children. The US Federal Drug Administration has issued what it calls a “black box warning” on the use of these drugs.
Why Was This Study Done?
The researchers wanted to discover whether the number of suicides in the US had increased or decreased since treatment with the first widely used SSRI (fluoxetine, also known as Prozac) began in 1988. Any difference in the number of suicides found before and after that date would not necessarily be the result of the introduction of this antidepressant, or other SSRIs, but the information would provide helpful information about the effects of these drugs.
What Did the Researchers Do and Find?
They looked at annual suicide rates between 1960 and 1988 and compared them with annual rates in the period 1988 to 2002. They used several sources of data, including the Centers of Disease Control and the US Census Bureau. The researchers found that from the early 1960s until 1988, in the entire US population, between 12.2 and 13.7 people in every 100,000 committed suicide each year. After that time, the numbers of suicides gradually declined, with the lowest figure (10.4 people per 100,000) reached in 2000. The researchers did mathematical tests, which demonstrated that the steady decline was statistically associated with the increased number of fluoxetine prescriptions—that is, the more prescriptions there were, the fewer suicides there were. (There were around two-and-a-half million prescriptions of the drug in 1988, increasing to over 33 million in 2002.)
What Do These Findings Mean?
In all scientific research, it is an important principle that finding an association between two events does not prove that one caused the other to occur. However, the authors of this paper suggest that the use of this drug could have contributed to the reduction of suicide rates in the US in the period 1988 to 2002. Several other SSRIs are also now in common use, but they were not considered in this study, nor were other antidepressants, or other treatments for depression.
Additional Information.
As depression is such a common condition—and because there are so many ways of treating it, including counseling and psychotherapy—there are many Web sites devoted to the subject. We have given a small selection below. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030190.
• From the American Academy of Family Physicians (AAFP), general advice on depression
• Also from the AAFP, advice specifically about antidepressant drugs
• MedlinePlus brings together authoritative information about depression from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations
• Health pages of the BBC on depression
• Information about depression from other UK health advice sites: Patient UK and NetDoctor.co.uk
doi:10.1371/journal.pmed.0030190
PMCID: PMC1475655  PMID: 16768544
12.  The relationship between the acute cerebral metabolic response to citalopram and chronic citalopram treatment outcome 
Objectives
The ability to identify the early neurobiological markers to predict the clinical response to a course of chronic psychotropic drug treatment motivated the early development of neurochemical brain imaging methods. The present study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater antidepressant response to twelve weeks of citalopram treatment in geriatric depression.
Methods
Sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40mg, IV). Then, the patients were treated with the oral medication for twelve weeks.
Results
Greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally) and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions.
Conclusions
Lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression.
PMCID: PMC3058257  PMID: 21218565
13.  Assessing the Comparative-Effectiveness of Antidepressants Commonly Prescribed for Depression in the US Medicare Population 
Background
Depression is among the most common chronic illnesses in the US elderly Medicare population, affecting approximately 11.5% of beneficiaries with estimated costs of about US$65 billion annually. Patients with depression are typically treated with antidepressants - most commonly the Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs vary substantially in their costs, side effect profiles and convenience of use. All these factors might affect medication adherence and subsequently down-stream medical costs.
Aims of Study
To assess the comparative-effectiveness of three antidepressants (escitalopram, citalopram, sertraline) commonly-prescribed for depression in Medicare.
Methods
We used pharmacy and medical claims data for a 5 percent national random sample of Medicare beneficiaries who were diagnosed with depression in 2008 and followed until 12/31/2009. Key measures included drug spending, medication adherence to antidepressants, down-stream non-drug medical costs at three levels: all, psychiatric and depression related costs. Three methods were conducted to test robustness: generalized linear regression (GLM), propensity score matching, and instrumental variables (IV) approach. For the instrumental variables approach, we used a two-stage residual inclusion model, using geographic variation in the use of the various drugs as instruments. Specifically, we calculated the ratio of the number of individuals who used each drug to the total number of individuals using any antidepressants at the 306 Dartmouth hospital-referral regions.
Results
The regression and the propensity score matching method each showed that patients using escitalopram had significantly worse adherence, higher drug costs, and higher medical costs than patients using either citalopram or sertraline. However, our IV analysis yielded different results. While drug costs remained significantly higher for escitalopram patients, we found that escitalopram users had lower non-drug medical spending than patients who used citalopram, which was enough to offset the higher drug costs. The instrumental variables results also suggested that sertraline users had lower non-drug medical costs than citalopram users. The differences between sertraline and escitalopram were not statistically significant for medical spending, but sertraline users had lower drug costs and better adherence than escitalopram users.
Discussion
The IV method yielded somewhat different results than the GLM regressions and the propensity score matching methods. Once we controlled for selection bias using the instrumental variables, we found that escitalopram is actually associated with lower medical spending. One interpretation is that the IV approach mitigates selection biases due to unobserved factors that are not controlled in regular regressions. However, one conclusion remains the same: in every model, we found that sertraline was at least as cost-effective as or more cost-effective than the other drugs.
Limitations
Potential unobserved factors affecting the choice of three antidepressants are possible.
Implications for Health Policies
All methods indicated that sertraline is the most cost-effective drug to treat depression. Substantial savings to Medicare could be realized by using more cost-effective antidepressants such as sertraline.
Implications for Further Research
Geographic variation in the use of prescription drugs has been underutilized as an instrumental variable in comparative-effectiveness research. Our study demonstrates that it can help to control for selection biases in observational data.
PMCID: PMC3608926  PMID: 23525835
Medicare; comparative-effectiveness research; depression; costs
14.  Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression 
Context
Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy.
Objective
To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI.
Design, Setting, and Participants
Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000–2006.
Interventions
Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20–40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150–225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy.
Main Outcome Measures
Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children’s Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time.
Results
Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%–62%) than a medication switch alone (40.5%; 95% CI, 33%–48%; P=.009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%–56% vs 47.0%; 95% CI, 40%–55%; P=.83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment.
Conclusions
For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.
doi:10.1001/jama.299.8.901
PMCID: PMC2277341  PMID: 18314433
15.  SSRI response in depression may be influenced by SNPs in HTR1B and HTR1A 
Psychiatric genetics  2009;19(6):281-291.
Desensitization of serotonin 1A (HTR1A) and 1B (HTR1B) autoreceptors has been proposed to be involved in the delayed onset of response to SSRIs. Variations in gene expression in these genes may thus affect SSRI response. Here we test this hypothesis in two samples from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and show evidence for involvement of several genetic variants alone and in interaction. Initially, three functional SNPs in the HTR1B gene and in the HTR1A gene were analyzed in 153 depressed patients treated with citalopram. QIDS-C scores were evaluated over time with respect to genetic variation. Subjects homozygous for the - 1019 G allele (rs6295) in HTR1A showed higher baseline QIDS scores (p = 0.033), and by 12 weeks had a significantly lower response rate (p = 0.005). HTR1B haplotypes were estimated according to previously reported in-vitro expression levels. Individuals who were homozygous for the high-expression haplotype showed significantly slower response to citalopram (p = 0.034).
We then analyzed more SNPs in the extended overall STAR*D sample. Although we could not directly test the same functional SNPs, we found that homozygotes for the G allele at rs1364043 in HTR1A (p = 0.045) and the C allele of rs6298 in HTR1B showed better response to citalopram over time (p = 0.022). Test for interaction between rs6298 in HTR1B and rs1364043 in HTR1A was significant (overall p = 0.032)
Our data suggest that an enhanced capacity of HTR1B or HTR1A transcriptional activity may impair desensitization of the autoreceptors during SSRI treatment.
doi:10.1097/YPG.0b013e32832a506e
PMCID: PMC2783179  PMID: 19829169
SSRI; depression; haplotype; HTR1B; HTR1A; association
16.  Variations in response to citalopram in men and women with alcohol dependence. 
OBJECTIVE: To examine the differential effects of citalopram on alcohol consumption in nondepressed women and men with mild to moderate alcohol dependence. DESIGN: Prospective, placebo-controlled study. PARTICIPANTS: Sixty-one subjects (34 men and 27 women). INTERVENTIONS: After a 2-week baseline, subjects were randomly assigned to 12 weeks of citalopram (40 mg per day) (n = 15 women, 16 men) or placebo (n = 12 women, 18 men). All received brief standard psychosocial interventions. OUTCOME MEASURES: Alcohol Dependence Scale, Montgomery-Asberg Depression Scale, Michigan Alcohol Screening Test, State-Trait Anxiety Inventory and daily alcohol intake. RESULTS: Pretreatment sex differences were evident in alcohol consumption, alcohol dependence, alcohol-related problems and on anxiety and depression measures. After treatment, analyses of covariance with depression and anxiety scores as covariates revealed a differential benefit of citalopram for men. Men receiving citalopram reduced average drinks per day by 44%, whereas women exhibited a 27% decrease (p < 0.05). CONCLUSIONS: Men may benefit more than women from citalopram in the treatment of alcohol dependence. These findings highlight the importance of examining sex as a significant variable in evaluating response to pharmacotherapy.
PMCID: PMC1407711  PMID: 10863887
17.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration 
PLoS Medicine  2008;5(2):e45.
Background
Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.
Methods and Findings
We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.
Conclusions
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.
Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients.
Editors' Summary
Background.
Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine.
Why Was This Study Done?
Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy.
What Did the Researchers Do and Find?
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.
What Do These Findings Mean?
These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050045.
The MedlinePlus encyclopedia contains a page on depression (in English and Spanish)
Detailed information for patients and caregivers is available on all aspects of depression (including symptoms and treatment) from the US National Institute of Medical Health and from the UK National Health Service Direct Health Encyclopedia
MedlinePlus provides a list of links to further information on depression
Clinical Guidance for professionals, patients, caregivers and the public is provided by the UK National Institute for Health and Clinical Excellence
doi:10.1371/journal.pmed.0050045
PMCID: PMC2253608  PMID: 18303940
18.  A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome 
Gut  2006;55(8):1095-1103.
Introduction
Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of irritable bowel syndrome (IBS) although evidence of their efficacy is scarce.
Aim
Twenty three non‐depressed IBS patients were recruited from a tertiary care centre and included in a crossover trial comparing six weeks of treatment with the SSRI citalopram (20 mg for three weeks, 40 mg for three weeks) with placebo. IBS symptom severity was the primary outcome measure, and depression and anxiety scores were also measured. The effect of acute administration of citalopram on colonic sensitivity and on colonic response to feeding was investigated as a putative predictor of symptomatic response to the drug.
Results
After three and six weeks of treatment, citalopram significantly improved abdominal pain, bloating, impact of symptoms on daily life, and overall well being compared with placebo. There was only a modest effect on stool pattern. Changes in depression or anxiety scores were not related to symptom improvement. The effect of acute administration of citalopram during a colonic barostat study did not predict clinical outcome. Analysis of the first treatment period as a double blind parallel arm study confirmed the benefit of citalopram over placebo.
Conclusions
The SSRI citalopram significantly improves IBS symptoms, including abdominal pain, compared with placebo. The therapeutic effect is independent of effects on anxiety, depression, and colonic sensorimotor function.
doi:10.1136/gut.2005.077503
PMCID: PMC1856276  PMID: 16401691
selective serotonin reuptake inhibitor; citalopram; irritable bowel syndrome
19.  Selective Serotonin Reuptake Inhibitor Suppression of HIV Infectivity and Replication 
Psychosomatic medicine  2010;72(9):925-932.
Objective
To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down regulate HIV infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/AIDS. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells (NK) cells and CD8+ lymphocytes, key regulators of HIV infection.
Methods
Ex-vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication, in 48 depressed and non-depressed women. For both the acute and chronic infection models, HIV reverse transcriptase (RT) activity was measured in the citalopram treatment condition and the control condition.
Results
The SSRI significantly downregulated the RT response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status.
Conclusions
These studies suggest that an SSRI enhances NK/CD8 non-cytolytic HIV suppression in HIV/AIDS and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.
doi:10.1097/PSY.0b013e3181f883ce
PMCID: PMC2978281  PMID: 20947783
Serotonin; Immunity; Depression; HIV/AIDS
20.  Escitalopram versus other antidepressive agents for depression 
Background
Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs remain the mainstay of treatment in primary and secondary care settings. During the last 20 years, antidepressant prescribing has risen dramatically in western countries, mainly because of the increasing consumption of selective serotonin reuptake inhibitors (SSRIs) and newer antidepressants, which have progressively become the most commonly prescribed antidepressants. Escitalopram is the pure S-enantiomer of the racemic citalopram.
Objectives
To assess the evidence for the efficacy, acceptability and tolerability of escitalopram in comparison with tricyclics, other SSRIs, heterocyclics and newer agents in the acute-phase treatment of major depression.
Search methods
Electronic databases were searched up to July 2008. Trial databases of drug-approving agencies were hand-searched for published, unpublished and ongoing controlled trials.
Selection criteria
All randomised controlled trials comparing escitalopram against any other antidepressant (including non-conventional agents such as hypericum) for patients with major depressive disorder (regardless of the diagnostic criteria used).
Data collection and analysis
Data were entered by two review authors (double data entry). Responders and remitters to treatment were calculated on an intention-to-treat basis. For dichotomous data, odds ratios (ORs) were calculated with 95% confidence intervals (CI). Continuous data were analysed using standardised mean differences (with 95% CI) using the random effects model.
Main results
Fourteen trials compared escitalopram with another SSRI and eight compared escitalopram with a newer antidepressive agent (venlafaxine, bupropion and duloxetine). Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93). Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to duloxetine, for discontinuation due to any cause (OR 0.62, 95% CI 0.38 to 0.99).
Authors’ conclusions
Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to treatment (after two weeks of treatment). Cost-effectiveness information is also needed in the field of antidepressant trials. Furthermore, as with most standard systematic reviews, the findings rely on evidence from direct comparisons. The potential for overestimation of treatment effect due to sponsorship bias should also be borne in mind.
doi:10.1002/14651858.CD006532.pub2
PMCID: PMC4164382  PMID: 19370639
Antidepressive Agents [*therapeutic use]; Citalopram [*therapeutic use]; Depression [*drug therapy]; Randomized Controlled Trials as Topic; Serotonin Uptake Inhibitors [*therapeutic use]; Humans
21.  Citalopram is not Effective Therapy for Non-Depressed Patients with Irritable Bowel Syndrome 
Background & Aims
Data are conflicting on the benefit of selective serotonin reuptake inhibitors (SSRIs) for patients with irritable bowel syndrome (IBS); the role of visceral sensitivity in IBS pathophysiology is unclear. We assessed the effects of citalopram and the relationships between, symptoms, and quality of life (QOL), and rectal sensitivity in non-depressed patients with IBS.
Methods
Patients from primary, secondary and tertiary care centers were randomly assigned to groups given citalopram (20 mg/day for 4 weeks, then 40 mg/day for 4 weeks) or placebo. The study was double masked with concealed allocation. Symptoms were assessed weekly; IBS-QOL and rectal sensation were determined from barostat measurements made at the beginning and end of the study.
Results
Patients that received citalopram did not have a higher rate of adequate relief from IBS symptoms than subjects that received placebo (12/27, 44% vs 15/27, 56% respectively; P=0.59), regardless of IBS subtype. The odds ratio for weekly response to citalopram vs placebo was 0.80 (95% confidence interval [CI] 0.61–1.04). Citalopram did not reduce specific symptoms or increase IBS-QOL scores; it had no effect on rectal compliance and a minimal effect on sensation. Changes in IBS-QOL score and pressure-eliciting pain were correlated (r=0.33, 95% CI 0.03–0.57); changes in symptoms and rectal sensitivity or IBS-QOL scores were not correlated.
Conclusions
Citalopram was not superior to placebo in treating non-depressed IBS patients. Changes in symptoms were not correlated with changes in rectal sensation assessed by barostat; Any benefit of citalopram in non-depressed IBS patients is likely to be modest.
doi:10.1016/j.cgh.2009.09.008
PMCID: PMC2818161  PMID: 19765674
22.  Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis  
Objective
Escitalopram is the most selective of the selective serotonin reuptake inhibitor (SSRI) antidepressants. Previous studies have suggested that escitalopram is superior to citalopram in efficacy. We conducted a meta-analysis of studies in which escitalopram was compared with other antidepressants to assess the relative efficacy of these agents.
Methods
Data from all randomized, double-blind studies in major depression in which escitalopram was compared with active controls (citalopram, fluoxetine, paroxetine, sertraline and venlafaxine XR [extended release]) were pooled. The 10 studies were conducted in both specialist settings and general practice. Patients met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), for major depressive disorder and were at least 18 years old. In all but 2 studies, patients were required to have a score of 22 or more on the Montgomery–Åsberg Depression Rating Scale (MADRS). The primary outcome measure was the estimated difference in treatment effect in MADRS total score at the end of the study. Secondary outcome measures were the response to treatment (defined as a ≥ 50% reduction in baseline MADRS total score) and remission rate (defined as MADRS total score ≤ 12 at end of study).
Results
A total of 2687 patients were included in the analyses (escitalopram n = 1345, conventional SSRIs n = 1102, venlafaxine XR n = 240). Escitalopram was superior to all comparators in overall treatment effect, with an estimated difference in treatment effect of 1.07 points (95% confidence interval [CI] 0.42–1.73, p < 0.01), and in response (odds ratio [OR] 1.29, 95% CI 1.07–1.56, p < 0.01) and remission (OR 1.21, 95% CI 1.01–1.46, p < 0.05) rates. In analysis by medication class, escitalopram was significantly superior to the SSRIs and comparable to venlafaxine, although the overall results do not necessarily reflect a significant difference between escitalopram and individual SSRIs. These results were similar in the severely depressed population (patients with baseline MADRS ≥ 30). The withdrawal rate due to adverse events was 6.7% for escitalopram compared with 9.1% for the comparators (p < 0.05).
Conclusions
In this meta-analysis, escitalopram showed significant superiority in efficacy compared with the active controls.
PMCID: PMC1413963  PMID: 16575428
depressive disorder, major; escitalopram; meta-analysis; serotonin uptake inhibitors; treatment outcome
23.  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
24.  Risperidone, quetiapine, and olanzapine adjunctive treatments in major depression with psychotic features: a comparative study 
Objectives
The purpose of this study was to compare the effectiveness of novel antipsychotics in the treatment of psychotic depression.
Method
Consecutive patients who were admitted (n = 51) with a confirmed diagnosis of major depression with psychotic features (delusions or hallucinations or both) participated in this open-label, naturalistic study. All patients were treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (citalopram or venlafaxine extended release [XR]), and atypical antipsychotic agents were added, as tolerated, during the first week of initiating the citalopram or venlafaxine. There were patients (n = 16) who received risperidone, who received quetiapine (n = 20), and who received olanzapine (n = 15), as an adjunctive treatment to either citalopram or venlafaxine for at least 8 weeks. Outcome measures included the Clinical Global Impression-Severity subscale (CGI-S), as the primary outcome measure, as well as the Hamilton Rating Scale for Depression-21 item (HAM-D21) and the Brief Psychiatric Rating Scale (BPRS). Tolerance to treatments and weight changes were monitored over the period of the trial.
Results
All patients completed the trial with no drop outs. At 8 weeks, there was a statistically significant (P < 0.001) clinical improvement in all outcome measures for both the depressive and psychotic symptoms, for all three groups of atypical adjunctive treatments. Utilizing analysis of variance (ANOVA), there were no significant differences between the three adjunctive treatment groups in outcome measures. The three antipsychotic agents were equally tolerated. At 8 weeks there was slight increase in weight in the three treatment groups, which was statistically significant (P > .01) in the olanzapine group.
Conclusion
Quetiapine, risperidone, and olanzapine, given as adjunctive treatment with SSRIS or SNRIs can significantly and equally improve depressive and psychotic symptoms, in the short-term treatment of major depression with psychotic features. The author recommends that large controlled trials be conducted to examine the differences in long-term efficacy and tolerance between the atypical antipsychotic agents, in the treatment of major depression with or without psychotic features.
doi:10.2147/NDT.S42745
PMCID: PMC3627471  PMID: 23596349
depression; novels; antipsychotics; treatment; augmentation
25.  Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study 
Osteoporosis International  2014;26:273-279.
Summary
Sixty patients diagnosed with generalized anxiety disorder and treated with either paroxetine, sertraline, or citalopram for at least 12 months were enrolled in this study, and the bone mineral density (BMD) of the patients was compared with that of 40 healthy volunteers. Selective serotonin reuptake inhibitor (SSRI) therapy in generalized anxiety disorder was found to be related with decreased BMD values.
Introduction
The objectives of this study were to evaluate the effect of SSRI therapy on BMD in postmenopausal women diagnosed with generalized anxiety disorder (GAD) and to identify the effects of the duration of disease and treatment on risk factors for osteoporosis.
Methods
Sixty patients diagnosed with GAD and treated with paroxetine, sertraline, or citalopram from the SSRI group for at least 12 months were enrolled. Social demographic features, the Hamilton Anxiety Scale (HAS) results, and the Hamilton Depression Scale (HDS) scores of all the patients were assessed. The BMD of the patients was measured by dual-energy X-ray absorptiometry (DXA) at the femoral and lumbar regions. The patients were divided into three groups which are the paroxetine, sertraline, and citalopram groups. The BMD of the patients was compared with that of 40 healthy volunteers.
Results
The L2–L4, total lumbar vertebrae, femoral intertrochanteric, total femoral Z-scores, and femoral Ward’s region T-scores of the treatment group were lower than the median T- and Z-scores of the control group (p < 0.05). Of the treatment groups, the femoral neck, trochanteric and intertrochanteric T- and Z-scores, total femoral T- and Z-scores, and femoral Ward’s T- and Z-scores of the sertraline group were significantly lower than the BMD values measured at the identical regions in the paroxetine and citalopram groups (p < 0.05).There was a significant negative correlation between the duration of treatment and the BMD values.
Conclusion
SSRI therapy in GAD was found to be related with decreased BMD values. Further randomized controlled studies are warranted to determine whether SSRI use is a risk factor for osteoporosis; such studies should investigate these factors by performing BMD assessments before treatment.
doi:10.1007/s00198-014-2859-2
PMCID: PMC4286623  PMID: 25187118
BMD; GAD; Osteoporosis; SSRI

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