Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor

Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a score > or =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total score < or =31 and >31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores < or =31 or >31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total score < or =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the >31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score >31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.     

N-methyl-citalopram: A quaternary selective serotonin reuptake inhibitor

We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [³H]citalopram and uptake studies with [³H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10⁻⁷ M as well as [³H]ketanserin binding to rat brain membranes at 10⁻⁵ M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.     

Clinical significance of selective serotonin reuptake inhibitor (SSRI) in the treatment of depression

SSRIs have had a great impact on the diagnosis and treatment of depression, as well as the search for its pathophysiology. Since SSRIs have relatively few adverse effects, it is also effective for treating in a mild forms of depression, which were formerly thought to be treated adequately with only psychotherapy or anti-anxietics. Recent studies on the natural history of depression have revealed the chronicity of this disease. SSRI is now the first-line drug for the continuation and maintenance therapy of depression. Since SSRI primary acts on the serotonergic system, wide use of this drug has questioned the postulated dichotomy of the biological hypothesis of depression, the so-called serotonin depression or norepinephrine depression. A new insight into the monoamine hypothesis of depression has been yielded by SSRI. SSRIs are also effective in the treatment of anxiety disorders such as obsessive-compulsive disorder, panic disorder and social phobia. Thus, SSRIs have also brought new insight into the role of serotonin in the pathophysiology of anxiety.     

哺乳期使用选择性5羟色胺再摄取抑制剂类抗抑郁药的安全性

抑郁症是哺乳期常见的疾病之一,目前关于哺乳期使用选择性5羟色胺再摄取抑制剂(SSRI)类抗抑郁药的安全性尚缺乏足够的证据。本文就哺乳期常用的SSRI类抗抑郁药安全性研究作一综述,并给出建议。     

Treatment of depression in acute coronary syndromes with selective serotonin reuptake inhibitors

Depression in patients with acute coronary syndromes (ACS) is common and associated with impaired cardiovascular prognosis in terms of cardiac mortality and new cardiovascular events. It remains unclear whether antidepressant treatment may reverse these effects. In this review, the literature is evaluated on (i) the antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with ACS; (ii) the pleiomorphic effects of SSRIs that may be associated with cardiovascular prognosis; and (iii) the effects of SSRIs on cardiovascular prognosis.SSRIs provide modest relief of depressive symptoms in selected subgroups of depressed patients with ACS. With respect to the pleiomorphic effects of SSRIs, three mechanisms of how SSRIs may improve cardiovascular prognosis are discussed: via platelet function, via the autonomic nervous system (ANS) and via vasomotor tone. Some studies show that SSRIs may reduce platelet activity and sympathetic nervous system activation, but results are inconclusive. SSRIs are associated with vasodilation but this needs to be confirmed with in vivo experiments. Some non-experimental studies describe favourable effects of SSRIs on cardiovascular prognosis. Despite recent developments, much of the effect of SSRIs on cardiovascular prognosis remains unclear. Although some studies suggest effects of SSRIs on platelet function, ANS and vasomotor tone, which may lead to improved cardiovascular prognosis, results are largely inconclusive. More well designed studies addressing these questions are needed. Moreover, since the effects of SSRIs on depression itself are limited, efforts should be dedicated to study the diagnostic validity and homogeneity of depression in the context of ACS and the presence of clinically relevant subtypes.     

An assessment of selective serotonin reuptake inhibitor discontinuation symptoms with citalopram

The selective serotonin reuptake inhibitors (SSRIs) have recently been associated with a variety of somatic and psychiatric symptoms upon abrupt drug discontinuation. These symptoms have been variously termed SSRI withdrawal, or SSRI discontinuation syndrome. Although all of the available SSRIs have been reported to cause discontinuation symptoms, some appear to have a greater propensity to cause these adverse events than others. Data from a previously completed placebo-controlled, double-blind study designed to assess citalopram in depression relapse prevention were analysed to assess patients for the emergence of discontinuation effects following randomization to placebo after 8 weeks of active drug treatment. Side-effects that occurred during the first 2 weeks following randomization to active drug (n = 150) or placebo (n = 72) were measured using the UKU unwanted side-effect list. The proportion of patients that experienced one or more events over the 2-week period following randomization was similar in the two groups, and there was no association between citalopram dose prior to randomization and the reporting of symptoms. Most of the events that did occur were mild in intensity and none resulted in discontinuation from the study. Events occurring at a higher frequency in the placebo group were most associated with the central nervous system (CNS). These events may reflect a re-emergence of depressive symptoms, since only 14.8% of patients randomized to placebo who did not relapse experienced CNS events, a low symptom incidence that was non-significant (P = 0.562) compared to patients continuing treatment (10.9%). Therefore, this assessment suggests that any symptoms associated with rapid discontinuation of citalopram are mild and transient, and emphasizes the significant role re-emerging depression and / or anxiety may play in the assessment and identification of SSRI discontinuation symptoms.     

Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression

Objective The aim of the investigation was to study the effects of withdrawing selective serotonin reuptake inhibitor (SSRI) drugs in nursing home patients, who had no documented diagnosis or symptoms of depression.Setting The setting of the study was in 11 nursing homes in the county of Stockholm, Sweden.Participants Participants were patients without dementia or history of depression who had received treatment with SSRI drugs for more than 6 months and who had no indications of anxiety disorder or major depressionDesign The included patients (n=70) were randomized to either the intervention group (withdrawal of SSRI) or the control group (no change in treatment), 35 patients to each group.Main outcome measures The patients were subjected to assessment using the following instruments: Montgomery-Åsberg depression rating scale, global assessment for functioning, health index and a symptom assessment form. Assessment was made at the start of the study and at the 3-month and 6-month follow-ups.Results We found no significant difference between the intervention and control groups in any outcome measure.Conclusion Treatment with SSRI drugs in patients without clinical major depression or anxiety disorder is often unjustified and should be discontinued.     

The economics of selective serotonin reuptake inhibitors in depression: a critical review

The prevalence of depression and the high costs associated with its treatment have increased interest in pharmacoeconomic evaluations of drug treatment, particularly in the 1990s as the use of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) expanded substantially. This review presents results from specific studies representing the key study designs used to address the pharmacoeconomics of SSRI use: retrospective administrative database analyses, clinical decision analysis models, and randomised clinical trials. Methodological considerations in interpreting results are highlighted. In retrospective administrative database analyses, most comparisons have been made between SSRIs and tricyclic antidepressants (TCAs). A few studies have addressed differences between SSRIs. The studies focused on healthcare cost (to payer) and cost-related outcomes (e.g. treatment duration, drug switching). Although SSRIs are generally associated with higher drug acquisition costs than are TCAs, total healthcare costs are at least offset, if not decreased, by reductions in costs associated with use of SSRIs. Although studies from the early 1990s show some advantage for fluoxetine, the results are limited by use of data from shortly after the introduction of paroxetine and sertraline; studies from the mid- 1990s on that compare drugs within the SSRI class show general equivalence in terms of cost. Important methodological advances are occurring in retrospective studies, with selection bias and other design limitations being addressed statistically. Clinical decision analysis models permit flexibility in terms of ability to specify different alternative treatment scenarios and varying durations. Sensitivity analysis aids interpretability, although model inputs are limited by data availability. Results from short term (1 year duration or less) studies comparing SSRIs and TCAs suggest that SSRIs are more cost effective or that there is no difference. Longer term studies (lifetime Markov models) focus more on the impact of maintenance antidepressant therapy and show more mixed results, generally favouring SSRIs over TCAs. The results indicate that the effect of SSRIs is mainly through prevention of relapse. Important assumptions of these models include fewer serious adverse effects and lower treatment discontinuation rates with SSRIs. Naturalistic clinical trials provide greater generalisability than traditional randomised clinical trials. One naturalistic trial found that nearly half of TCA-treated patients switched to another antidepressant within 6 months; only 20% of SSRI-treated patients switched. Cost differences between groups were minimal. These studies indicate few differences in medical costs, depression outcomes and health-related quality of life between TCAs and fluoxetine, although fewer fluoxetine-treated patients switched treatment.     

Pharmacogenetics of selective serotonin reuptake inhibitor response: a 6-month follow-up

BACKGROUND: We previously reported the association between some genetic factors and short-term antidepressant outcome. In the present paper we investigated the same gene variants in a prospective 6-months naturalistic follow-up. METHODS: The sample included 185 inpatients affected by recurrent major depression consecutively admitted to the Psychiatric Inpatient Unit of San Raffaele Hospital from 1998 to 2003 and prospectively followed for 6 months after their recovery. All the patients were undertaking continuation therapy. The functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR), the tryptophan hydroxylase A218C substitution, a VNTR polymorphism located 1.2 kb upstream of the monoamine oxidase-A coding sequences, the CLOCK gene T3111C and the PER3exon15 gene T1940G substitutions were analysed, using PCR-based techniques. RESULTS: No association was found between clinical variables and relapses; subjects showing TT genotype at CLOCK gene tended to relapse within 6 months after recovery more than TC and CC subjects taken together. A non-significant tendency of SERTPR*s/s subjects to a minor frequency of relapse was also observed. CONCLUSION: Some subjects showing remission after acute treatment relapsed within 6 months, despite undertaking a maintenance treatment; the causes could be heterogeneous, but CLOCK gene variants may influence the outcome.     

Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are widely used for psychiatric complications after stroke. Studies have indicated additional effects, and SSRIs could potentially be used as enhancers of stroke recovery. However, beneficial effects should be weighed against potential adverse effects. In particular, the possible association with cerebrovascular events has raised concern.

Areas covered: We review the literature on cerebrovascular events associated with SSRI treatment after stroke. The possible beneficial effects of SSRI treatment for stroke recovery and survival, and potential safety concerns, are discussed.

Expert opinion: Evidence suggests that SSRIs may enhance stroke recovery. Most studies on cerebrovascular risk are from non-stroke populations and little is known about recurrent events and mortality post-stroke. In non-stroke populations treatment has been associated with increased risk of intracerebral and intracranial hemorrhage; however the absolute risk is low. The association between SSRIs and ischemic stroke is less clear. Randomized stroke trials indicate that treatment is safe and well tolerated, and the most common side effects are often benign and transient. The trials are small however and not powered to detect potential differences in cerebrovascular events. We await several ongoing large randomized trials before SSRIs can be recommended as a routine pharmacotherapy in stroke recovery.