S. Montgomery

Comparison of compliance between serotonin reuptake inhibitors and tricyclic antidepressants : a meta-analysis

A meta-analysis of 67 published randomized controlled clinical trials comparing selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), which measured discontinuation rates for side effects and lack of efficacy, was performed. All multiple publications and trials using non-TCA comparators were excluded. Ten studies were placebo controlled; these were analysed separately. Overall, the difference in withdrawals due to side effects of SSRIs and TCAs was - 4.5% (p = 0.0004) and that due to lack of efficacy was 0.1% (p = 0.86). In the placebo-controlled trials the differences between the two groups were - 7.9% and - 0.1 % (p = 0.06 and 0.96), respectively. These results demonstrate that SSRIs have a significant and clinically important advantage over TCAs with respect to tolerability, whereas efficacy is similar. Treatment failure due to poor compliance can increase health-care costs: therefore, in selecting an antidepressant for the first-line treatment of major depressive disorders, the risks, benefits and costs of each type of treatment need to be critically evaluated.

Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder

Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder (OCD). This double-blind, placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors, citalopram, in OCD. A total of 401 patients were randomized to receive citalopram 20, 40 or 60 mg/day or placebo for 12 weeks. All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) change score (P < 0.01). The highest response rate, defined as 25% improvement in Y-BOCS entry score, was observed in the 60 mg group (65%). This compared with 52% and 57.4% in the 40 mg and 20 mg groups. Response rate on placebo was 36.6% (P < 0.05 for all three doses of citalopram compared to placebo). There was no significant difference between the individual doses of citalopram. An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo (P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities). Citalopram was well tolerated; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events.

Predictors of response to pharmacotherapy with citalopram in obsessive-compulsive disorder

Although serotonin reuptake inhibitors (SRIs) are the medications of choice in the treatment of obsessive-compulsive disorder (OCD), only 50-60% of patients respond to a single trial of any of these agents. Improved knowledge of the predictors of response to treatment may have important clinical implications. Data from a large randomized placebo-controlled trial of citalopram in OCD was analysed using logistic regression to determine predictors of response. Demographic (age, sex), clinical (OCD severity and duration, depression severity, prior treatment) and trial variables (citalopram dose, treatment duration) were included. Subjects with longer duration of OCD, more severe OCD symptoms or previous selective SRI use were less likely to be responders in the citalopram trial. In contrast, subjects who received adequate medication doses for sufficient periods of time in the citalopram trial were more likely to be responders. Despite greater awareness of OCD in recent years, there is evidence that the disorder continues to be underdiagnosed and undertreated. The data here emphasize the crucial importance of early diagnosis and treatment of OCD, and of pharmacotherapy with appropriate dose and duration.

Moclobemide is effective and well tolerated in the long-term pharmacotherapy of social anxiety disorder with or without comorbid anxiety disorder.

Social phobia (social anxiety disorder) is a highly prevalent and chronic disorder that is associated with significant comorbidity and disability. Despite recent advances in the pharmacotherapy of the disorder, there is a paucity of randomized controlled trials on patients with comorbid disorders and on maintenance treatment. A randomized placebo-controlled, double-blind multi-site trial of moclobemide, a reversible inhibitor of monoamine oxidase A, was undertaken with 390 subjects. After an initial 12 weeks, there was the option of continuing for an additional 6 months of treatment. The primary efficacy parameter chosen was responder status as defined by the Clinical Global Impression scale change item. From week 4 onwards, there was a significantly higher response rate on moclobemide than on placebo. Superiority of medication over placebo was similar in patients with comorbid anxiety disorders (33% of subjects) and without, as well as in patients with different subtypes of social anxiety disorder; indeed, treatment with moclobemide rather than placebo was the strongest predictor of response. Adverse events were similar across treatment groups, and were typically mild and transient. In the extension phase, response rates remained higher in the moclobemide group, and ratings of tolerability were equally high in both groups. Thus, in a large sample of social anxiety disorder patients with and without comorbid anxiety disorders, moclobemide was both effective and well-tolerated in the short as well as long-term. These data confirm and extend previous findings on the value of moclobemide in the treatment of social anxiety disorder, and strengthen the range of therapeutic options for managing this important disorder.

Social phobia : long-term treatment outcome and prediction of response : a moclobemide study

In this open, prospective, structured, naturalistic study of the efficacy of long-term treatment in social phobia 93 consecutive outpatients suffering from severe generalized or circumscribed social phobia (median Liebowitz. Social Anxiety Scale score 83) and a high degree of concomitant psychiatric disease were administered treatment with moclobemide (712 ± 75 mg/day at steady state). Fifty-nine patients who responded (Clinical Global Impression for Change: very much/much improved) completed 2 years of treatment. Patients then entered a drug-free period of at least 1 month during which 88% of the patients deteriorated. In a further 2-year treatment period with moclobemide those patients who had deteriorated became responders again. Symptoms reeurred in a substantial number of the patients at the end of the study when the dose was reduced and then discontinued. Post-study follow up at 6–24 months after study completion found that 63.2% of patients were almost asymptomatic or had only mild symptoms, 15.8% were off all treatment. 28.1% were back on moclobemide, 10.6% were taking another psychotropic drug and 8.8% were in psychotherapy. All previous non-responders to moelobemide and mostly alcohol abusers (36.9%), had moderate or severe social phobia and were off all treatment (13.3%), on psychotherapy (15.9%) or on another psychotropic drug (8.8%). Discriminant analysis correctly predicted outcome in 93.5% of all patients.Alcohol abuse was by far the strongest predictor of negative outcome. Coexisting generalized anxiety disorder and dysthymia were less potent in this regard, whereas high baseline Hamilton anxiety or depression scale scores, circumscribed social phobia, or social phobia unassociated with avoidant personality disorder were predictors of a positive outcome. In conclusion, severe social phobia can be successfully treated in the long-term but many patients may need medication or psychotherapy for many years. Treatment should start as early as possible because complications such as alcohol abuse make treatment difficult.

Antidepressant efficacy in relation to item analysis and severity of depression : a placebo-controlled trial of fluvoxamine versus imipramine

In this investigation, the antidepressant efficacy of fluvoxamine and imipramine was compared in a randomized, double-blind, placebo-controlled study lasting 4 weeks; 338 depressed patients were recruited at five North American centres. For the efficacy analyses an intent-to-treat sample was defined. The global efficacy of the two drugs was assesssed by the Hamilton Depression scale (HAM-D) and Clinical Global Impression (CGI) scores. Antidepressant activity was also assessed using the percentage of responders on the CGI “improvement” scale. In addition the time of onset of antidepressant effect was evaluated by weekly analysis of individual HAM-D items. The intent-to-treat sample was stratified retrospectively according to the severity of the depression (mild, moderate or severe). Regarding global efficacy, compared with placebo, only fluvoxamine significantly improved the HAM-D total scores at Week 4 (p < 0.05). There was a suggestion from individual HAM-D item scores (depressed mood, suicide, psychic anxiety) that fluvoxamine had an earlier effect than imipramine. Overall, compared with placebo, more HAM-D items were improved by fluvoxamine than imipramine. Fluvoxamine but not imipramine was significantly superior to placebo in severely depressed patients as shown by improvements in the HAM-D score (p < 0.01) and the CGI “improvement” score (p < 0.05). Side effect profiles for the active agents were typical for their pharmacological category: imipramine was associated with anticholinergic effects, particularly dry mouth, and fluvoxamine was associated with nausea and vomiting.

Depression: a long-term illness and its treatment.

Depression is a common illness that is frequently chronic or recurring. It is associated with substantial disability and therefore treatment strategies need to take into account its long-term course. The risk of relapse can be reduced provided therapy is adequate, in terms of both duration and dose, and there is now good evidence for some antidepressants that long-term treatment also reduces the risk of recurrence (i.e. new episodes of depression). This aspect of efficacy has been investigated most thoroughly with the tricyclic antidepressant imipramine and with the selective serotonin reuptake inhibitors. The clearest demonstration of the ability to reduce the risk of new episodes of depression is obtained from studies designed to test prophylaxis specifically in patients who have responded to antidepressant treatment and who have maintained their response during a period of continuation treatment to ensure resolution of the episode. The long-term efficacy of imipramine and fluoxetine was demonstrated using this design. More recently fluvoxamine was shown to be effective in reducing the risk of new episodes in a 1-year study in patients whose acute episode of depression had responded to treatment with fluvoxamine and who had remained well for 18 weeks. These prophylactic studies show that antidepressants reduce the risk of new episodes of depression, and prophylactic treatment should therefore be continued as long as the risk persists.

Neuronal cell adhesion genes and antidepressant response in three independent samples

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

ECNP Consensus Meeting, March 2003. Guidelines for the investigation of efficacy in social anxiety disorder

. Noyes, R., Moroz, G., Davidson, J.R., Liebowitz, M.R., Davidson, A., Siegel, J., Bell, J., Cain, J.W., Curlik, S.M., Kent, T.A., Lydiard, R.B., Mallinger, A.G., Pollack, M.H., Rapaport, M., Rasmussen, S.A., Hedges, D., Schweizer, E., Uhlenhuth, E.H., 1997. Moclobemide in social phobia: a controlled dose– response trial. J. Clin. Psychophar-

P.2.b.035 The combined effect of genetic polymorphisms and clinical parameters on treatment response and resistance in major depressive disorder

BDNF and PDYN (p< 0.05, Spearman r = 0.2017) and an inverse correlation with two PDYN SNPs (rs1997794 and rs2281285). Conclusions: Our results are consistent with the epigenetic theory of psychosis, supporting the importance of alterations of epigenetic mechanisms in the etiology of BD and MDD. They also provide a new and clear correlation between changes in the epigenetic level of the BDNF and PDYN gene, suggesting their interaction in the development of BD. We also confirm that the use of PBMCs could be exploited as a reliable model of the complex epigenetic mechanisms leading to the discovery of biomarkers of diseases. Finally, we further suggest the relevance of integrating data on genetic variants and DNA methylation.