Whether the acute outcomes of major depressive disorder (MDD) treated in primary (PC) or specialty care (SC) settings are different is unknown.
To compare the treatment and outcomes for depressed outpatients treated in primary versus specialty settings with citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org), a broadly inclusive effectiveness trial.
Open clinical trial with citalopram for up to 14 weeks at 18 primary and 23 specialty sites. Participants received measurement-based care with 5 recommended treatment visits, manualized pharmacotherapy, ongoing support and guidance by a clinical research coordinator, the use of structured evaluation of depressive symptoms and side effects at each visit, and a centralized treatment monitoring and feedback system.
A total of 2,876 previously established outpatients in primary (n = 1091) or specialty (n = 1785) with nonpsychotic depression who had at least 1 post-baseline measure.
Measurements and Main Results
Remission (Hamilton Depression Rating Scale for Depression [Hamilton] or 16-item Quick Inventory of Depressive Symptomatology-Self-Rated [QIDS-SR16]); response (QIDS-SR16); time to first remission (QIDS-SR16). Remission rates by Hamilton (26.6% PC vs 28.0% SC, p = .40) and by QIDS-SR16 (32.5% PC vs 33.1% SC, p = .78) and response rates by QIDS-SR16 (45.7% PC vs 47.6% SC, p = .33) were not different. For those who reached remission or response at exit, the time to remission (6.2 weeks PC vs 6.9 weeks SC, p = .12) and to response (5.5 weeks PC vs 5.4 weeks SC, p = .97) did not differ by setting.
Identical remission and response rates can be achieved in primary and specialty settings when identical care is provided.
primary care; depression; clinical trial; outcomes
We sought to determine whether clinical response or tolerance to the Selective Serotonin Reuptake Inhibitor (SSRI) citalopram is associated with genetic polymorphisms in potentially relevant pharmacokinetic enzymes.
We used a two-stage case-control study design in which we split the sample of 1,953 subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial into a discovery (n = 831) and validation set (n = 1,046). Fifteen polymorphisms from five (CYP2D6, ABCB1, CYP2C19, CYP3A4, and CYP3A5) pharmacokinetic genes were genotyped. We examined the associations between these polymorphisms and citalopram response and tolerance. Significant associations were validated in the second stage for those polymorphism found to be statistically significant in the first stage.
No genetic polymorphism in the pharmacokinetic genes examined was significantly associated with our response or tolerance phenotypes in both stages. For managing pharmacological treatment with citalopram, routine screening of the common pharmacokinetic DNA variants that we examined appears to be of limited clinical utility.
Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of irritable bowel syndrome (IBS) although evidence of their efficacy is scarce.
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.
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.
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.
selective serotonin reuptake inhibitor; citalopram; irritable bowel syndrome
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.
SSRI; depression; haplotype; HTR1B; HTR1A; association
The purpose of this study was to compare the effectiveness of novel antipsychotics in the treatment of psychotic depression.
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.
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.
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.
depression; novels; antipsychotics; treatment; augmentation
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.
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.
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.
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.
Little is known about treating elderly suicidal patients with schizophrenia. The purpose of this article is to review the literature dealing with this population and to discuss what is required to advance this field. Most available studies from middle-aged and older individuals suggest that risk factors include hopelessness, lower quality of life, past traumatic events, depressive symptoms, lifetime suicidal ideation and past attempts; it is not clear whether these findings are generalizable to geriatric populations. Although little treatment research has been performed in older suicidal patients with schizophrenia, an integrated psychosocial and pharmacologic approach is recommended. In addition, one recent study augmented antipsychotic treatment with an SSRI (i.e., citalopram) in a sample of middle-aged and older individuals with schizophrenia with subsyndromal depression; in that study, serotonin selective reuptake inhibitor augmentation reduced depressive symptoms and suicidal ideation. More research is required to better understand suicidal behavior in older patients with schizophrenia.
antidepressant; antipsychotic; depression; elderly; geriatric; risk factor; schizophrenia; SSRI; suicide; treatment
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.
selective serotonin reuptake inhibitors; citalopram; serotonin; positron emission tomography (PET); glucose metabolism; sex differences; aging
Treatment with selective serotonin reuptake inhibitors (SSRI) is one of the most common treatments for depression. It is however not clear whether or not there is an increased short-term suicide risk during initiation with SSRI.
A register-based nationwide case-crossover study including 5,866 suicides, 1,698 women and 4,168 men, from the Death Register 2007-2010 in Sweden. SSRI initiation was defined as a dispensed prescription of SSRI within 28 days prior to the date of suicide with no previous dispensed prescription of SSRI within 4 months prior that prescription. The control period took place one year earlier. Odds ratio (OR) was estimated using conditional logistic regression.
During the 28 day period prior to suicide 48 women and 138 men were exposed to SSRI initiation (while not being exposed in the control period) and 22 women and 43 men were exposed in the control period (while not being exposed in the case period). The OR for suicide after initiation with SSRI was 2.7 (95% CI: 1.6-44) for women, and 4.3 (95% CI: 3.0-6.1) for men. The highest OR was found 8-11 days after initiation with SSRI 9.7 (95% CI: 3.0-31.7) for women and men combined.
The main limitation in this study is confounding by indication, but the descriptive question is however not confounded by indication. Together with plausible biological mechanisms and previous clinical and epidemiological observations our findings, linking initiation of SSRI to increased short-term suicide risk, deserve further attention specifically in the clinical setting.
We applied a systematic pharmacogenetic approach to investigate the role of genetic variation in the gene encoding catechol O-methyltransferase (COMT) in individual variation in selective serotonin reuptake inhibitor (SSRI) response among depressed patients. Twenty-three single nucleotide polymorphisms (SNPs) in COMT were genotyped using DNA from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (N=1914). One SNP, rs13306278, located in the distal promoter region of COMT, showed significant association with remission in White Non-Hispanic (WNH) subjects (P = 0.038). Electromobility shift assay for rs13306278 showed alternation in the ability of the variant sequence to bind nuclear proteins. A replication study was performed using samples from the Mayo Clinic PGRN Citalopram/Escitalopram Pharmacogenomic study (N=422) that demonstrated a similar trend for association. Our findings suggest that novel genetic markers in the COMT distal promoter may influence SSRI response phenotypes.
Pharmacogenetics; catechol O-methyltransferase; COMT; selective serotonin reuptake inhibitor; major depressive disorder; STAR*D
A subset of patients undergoing initial antidepressant treatment experience worsening of symptoms, including thoughts of suicide or suicidal behavior. The present study explores whether this subset of patients is also more likely to experience recurrence or worsening of these symptoms during a second treatment trial with a different antidepressant.
We examined data collected between July 2001 and September 2006 from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter effectiveness study of outpatients with major depressive disorder diagnosed by a DSM-IV checklist. In that study, subjects who did not remit with citalopram treatment were randomized among next-step treatment options. The main outcome measure for this post hoc analysis, presence of suicidal thoughts and behaviors, was assessed using the suicide item on the 16-item Quick Inventory of Depressive Symptomatology—Self-Rated. Logistic regression was used to examine association between emergence or worsening of these symptoms with the first-step (level 1) citalopram treatment and emergence or worsening with next-step (level 2) pharmacologic or psychosocial treatment, including augmentation with bupropion or buspirone; switch to sertraline, venlafaxine, or bupropion; or addition of or switch to cognitive therapy.
Of 1,240 subjects entering level 2 with a score less than 3 on the suicide item, 102 (8.2%) experienced emergence or worsening of suicidal thoughts or behaviors. Emergence or worsening at level 1 was strongly associated with reemergence or worsening at level 2 (crude OR=4.00 [95% CI, 2.45–6.51], adjusted OR=2.95 [95% CI, 1.76–4.96]). Overall magnitude of risk was similar among next-step pharmacologic augmentation versus switching.
These results suggest that individuals who experience emergence or worsening of suicidal thoughts or behaviors with one antidepressant treatment may warrant closer follow-up during the next-step treatment, as these symptoms may recur regardless of which modality is selected.
Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans.
We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment.
Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect.
Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.
Antidepressants; depression; fMRI; reward; SSRI; ventral striatum
The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs that use psychostimulant “cognitive enhancers”. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2–5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factors zif 268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction liability of methylphenidate.
psychostimulant; immediate-early gene; caudate-putamen; rat
Obsessive-compulsive disorder (OCD) is a common and severe neuropsychiatric disorder treated by both behavioral and pharmacologic techniques. Despite the availability of treatments for OCD, including the selective serotonin reuptake inhibitors (SSRIs), many OCD patients have an inadequate response to current treatments. As such, additional approaches to the management of OCD are required. A potential but little studied treatment for OCD is the SSRI escitalopram. Escitalopram is the S-enantiomer of citalopram, the preparation containing both S and R enantiomers of citalopram. Not only is escitalopram the most selective of the SSRIs, it is also devoid of R-citalopram, which may interfere with the effects of the S enantiomer. Escitalopram appears to be effective in depression and several anxiety disorders, including social anxiety disorder and generalized anxiety disorder, conditions in which it also appears reasonably well tolerated. Enantiomeric specificity, high serotonin reuptake selectivity, comparatively good tolerability and favorable pharmacokinetics, and preliminary evidence of efficacy in OCD suggest a potential role for the use of escitalopram in the treatment of OCD. Nevertheless, additional work including evaluating the use of escitalopram with behavioral interventions and in long-term treatment of OCD is needed to clarify its overall role in managing OCD.
escitalopram; obsessive-compulsive disorder; pharmacotherapy
Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain.
Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition.
Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.
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.
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.
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.
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.
Serotonin; Immunity; Depression; HIV/AIDS
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.
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).
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.
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.
schizophrenia; citalopram; depression; functioning; social skills
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.
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.
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.
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.
CEA; depression; escitalopram; Lombardy; ICER; SSRI
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.
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.
University affiliated outpatient psychiatry clinics.
One hundred seventy-four community dwelling men and women 75 years or older with non-psychotic unipolar depression.
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).
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.
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.
cognitive functioning; cognitive impairment; geriatric depression; late-life depression; citalopram
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.
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.
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.
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.
Sleep disturbances and symptoms of depression are common during pregnancy. Both are independent and interrelated risk factors for adverse outcomes. It is unclear the degree to which sleep differs between depressed and non-depressed pregnant women. We sought to 1), describe and compare sleep disturbances in depressed pregnant and non-depressed pregnant women, 2) determine the impact of selective serotonin reuptake inhibitors (SSRI) treatment on sleep, and 3)evaluate whether sleep at 20 weeks is associated with increased depressive symptoms and major depressive disorder (MDD) in later pregnancy.
Pregnant women (N = 240) were recruited in the second trimester (20 weeks gestation) and assigned to depressed (N = 59) and non-depressed (N = 181) groups based on a SCID diagnosis of major depressive disorder. The Structured Interview Guide for the Hamilton Rating Scale with Atypical Depression Supplement (SIGH-ADS) was administered at 20, 30 and 36 weeks gestation from which the sleep variables were obtained.
Depressed women had more fragmented sleep at each assessment (p values ≤ .05). However, the frequency of insomnia symptoms was greater for depressed women only at 20 weeks gestation. SSRI use, regardless of MDD status, did significantly affect several sleep variables. Among the non-depressed women, those with short or longer sleep duration, symptoms of insomnia and long periods of nocturnal waketime had higher SIGH-ADS scores later in pregnancy (p values = < .05).
At 20 and 30 weeks gestation sleep was more disturbed in depressed pregnant women compared to non-depressed pregnant women. At 36 weeks, sleep was disturbed regardless of depression status or SSRI use. Among the non-depressed women, disturbed sleep in conjunction with SSRI use was associated with higher depressive symptoms.
Sleep; depression; pregnancy; women; SIGH-ADS; insomnia; SSRI
Suicidal ideation is an uncommon but worrisome symptom than can emerge during antidepressant treatment. We have previously described association between treatment emergent suicidal ideation (TESI) and markers in genes encoding the glutamate receptors GRIK2 and GRIA3. The present genome-wide association study was conducted to identify additional genetic markers associated with TESI that may help identify individuals at high-risk who may benefit from closer monitoring, alternative treatments, and/or specialty care. A clinically-representative cohort of outpatients with non-psychotic major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 90 white participants who developed TESI and a gender and race matched equal number of treated participants who denied any suicidal ideas were genotyped with 109,365 single nucleotide polymorphisms on the Illumina's Human-1 BeadChip. One marker was found to be associated with TESI in this sample at the experiment-wide adjusted p<0.05 level (marker rs11628713, allelic p= 6.2 × 10-7, OR = 4.7, permutation p=0.01). A second marker was associated at the experiment-wide adjusted p=0.06 level (rs10903034, allelic p = 3.02× 10-6, OR = 2.7, permutation p=0.06). These markers reside within the genes PAPLN and IL28RA, respectively. PAPLN encodes papilin, a protoglycan-like sulfated glycoprotein. IL28RA encodes an interleukin receptor. Together with our previous report, these findings may shed light on the biological basis of TESI and may help identify patients at increased risk of this potentially serious adverse event.
treatment-emergent suicidal ideation; TESI; pharmacogenetics; citalopram; antidepressant; major depression; SSRI; STAR*D; genome-wide
This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.
major depressive disorder; adolescents; plasma concentration; drug exposure; optimization
The purpose of this study was to investigate the relationships of chronic stress, social undermining, and social support with symptom reduction and remission in depressed patients treated with antidepressant medication (citalopram), and to determine whether these relationships were moderated by ethnicity. A sample of 301 treatment-seeking adult patients with non-psychotic depression, including 169 African-American and 132 Caucasian men and women, were enrolled in an eight week, dose escalation clinical trial. Intent-to-treat analyses indicated that, consistent with expectations, more baseline social support was associated with greater symptom reduction and higher likelihood of remission, especially at higher levels of social undermining. Additionally, increases in social support from baseline to last visit were associated with more symptom reduction and higher likelihood of remission. However, contrary to expectations, higher levels of baseline social undermining were associated with more symptom reduction in Caucasians, but not in African-Americans. Results supported the treatment enhancing effect of available social support at the beginning of treatment and over the course of treatment. Efforts to enhance social support for patients on antidepressants should be considered as part of comprehensive treatment.
antidepressant; depression; ethnicity; psychosocial; stress; social support
The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.
Fluoxetine; sertraline; paroxetine; fluvoxamine; citalopram; escitalopram; intraocular pressure; side effects.