David Rossini

Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression.

BACKGROUND It has been recently reported that the short variant of the serotonin transporter (5-HTT) gene-linked functional polymorphic region (5-HTTLPR) influences the antidepressant response to certain selective serotonin reuptake inhibitors. The aim of the present study was to test this finding in a sample of major and bipolar depressives, with or without psychotic features. METHODS One hundred fifty-five inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Allelic variation of 5-HTTLPR in each subject was determined using a polymerase chain reaction-based technique. RESULTS 5-HTTLPR short variant was associated with a poor response to fluvoxamine treatment, independently from the recorded clinical variables. More specifically, the diagnosis, the presence of psychotic features, and the severity of depressive symptomatology did not influence this association. Conversely, pindolol augmentation may ameliorate the rate of response in 5-HTTLPR short variant subjects, thus reducing the difference in the response rate among the genotype variants. CONCLUSIONS If confirmed, these results may improve patient care by helping the clinician to individualize treatment according to the patients genetic 5-HTTLPR pattern.

Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity

The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject by using a PCR-based technique. No significant finding was observed in the overall sample as well as in the pindolol group, while TPH*A/A was associated with a slower response to fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect was independent from the previously reported influence of 5-HTTLPR polymorphism. If confirmed, these results may shed further light on the genetically determined component of the response to pharmacological treatments, thus helping the clinician to individualize each patients therapy according to their genetic pattern.

Tryptophan hydroxylase gene associated with paroxetine antidepressant activity.

The possible association of the A218C tryptophan hydroxylase (TPH) gene variant with the antidepressant activity of paroxetine was investigated in a sample of 121 inpatients affected by a major depressive episode and treated with paroxetine 20-40 mg with either placebo or pindolol in a double blind design for 4 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject using a PCR-based technique. TPH*A/A and TPH*A/C variants were associated with a poorer response to paroxetine treatment when compared to TPH*C/C (P=0.005); this difference was not present in the pindolol augmented group. Other variables, such as sex, diagnosis, presence of psychotic features, severity of depressive symptomatology at baseline and paroxetine plasma level, were not associated with the outcome. TPH gene variants are therefore a possible modulator of paroxetine antidepressant activity.

Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity

The aim of the present study was to test a possible effect of the monoamine oxidase A (MAOA) and serotonin receptor 2A (5-HT-2A) gene variants on the antidepressant activity of fluvoxamine and paroxetine in a sample of major (n = 248) and bipolar (n = 195) depressives, with or without psychotic features. A total of 443 in-patients were treated with 300 mg fluvoxamine (n = 307) or 20-40 mg paroxetine (n = 136) for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). Allele variants were determined in each subject using a PCR-based technique. We observed a marginal association between 5-HT-2A variants and antidepressant response while MAOA genotypes were not associated. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, HAMD scores at baseline, pindolol augmentation and SSRIs plasma levels did not significantly influence the observed results. The investigated MAOA and 5-HT-2A gene variants, therefore, do not seem to play a major role in SSRI antidepressant activity.

SSRIs antidepressant activity is influenced by Gβ3 variants

Abstract The aim of the present study was to test a possible effect of the G-protein β3-subunit (Gβ3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day ( n =362) or paroxetine 40 mg/day ( n =128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Gβ3 allelic variants were determined in each subject using a PCR-based technique. Subjects with Gβ3 T/T variants showed better response to treatment ( P =0.009) and this effect was independent from analyzed demographic and clinical variables. These results confirm preliminary reports and shed further light on the genetics of the response to antidepressant treatments.

Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders

We reported an independent association of the short variant of the serotonin transporter gene‐linked polymorphic region (SERTPR) and tryptophan hydroxylase (TPH) genes with antidepressant response to selective serotonin reuptake inhibitors (SSRIs). The aim of the present study was to confirm the effect of the SERTPR and TPH gene variants on the SSRIs antidepressant activity in a new sample of major and bipolar depressives. Two hundred and twenty one inpatients (major depressives = 128, bipolar disorder = 93) were treated with SSRIs (fluvoxamine or paroxetine) for 6 weeks; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression (HAMD). SERTPR and TPH variants were determined using PCR‐based techniques, 220 subjects genotyped for SERTPR and 221 for TPH that were never included in previous studies. SERTPR*s/s variant association with a poor response to SSRI treatment was confirmed, even if with less significant P values (P = 0.034), independently from clinical variables; pooling the present sample with previous ones we observed a highly significant effect (P < 0.000001). TPH*A/A variants showed higher HAMD scores throughout the trial but with only a trend in the same direction of our previous study in terms of a worse response of A/A genotypes. Thus, the previous positive association was not fully replicated for TPH. The present independent replication confirms SERTPR variants as a liability factor for antidepressant efficacy while the TPH effect is not unequivocal.

Response to SSRIs and role of the hormonal therapy in post-menopausal depression.

The aim of this study is to prospectively evaluate the antidepressant response to SSRIs in depressed post-menopausal women with or without hormonal therapy (HT), and to analyze the possible influence of basal serum levels of gonadotropins and sexual hormones on the antidepressant response. 170 post-menopausal women with a depressive episode (DSM-IV criteria)--47 on HT and 123 not on HT--started the treatment with an SSRI. Depressive symptoms were assessed at baseline and 7 weeks thereafter by raters blind to treatment regimen. Response rates were 63.2% in the group without HT and 83.7% in the HT group (p=0.013). An inverse correlation emerged between the basal levels of LH and the improvement in HRSD scores (p=0.001) in the group without HT. In conclusion, HT appeared to improve the antidepressant response to SSRIs. Furthermore, in post-menopausal women, LH basal levels may be taken into account as possible predictor of response.

No association between dopamine D2 and D4 receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors

Abstract The possible association of the dopamine receptor D 2 (Ser 311Cys) and D 4 exon 3 (48 base pair repeat) gene variants with the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) was investigated in a sample of 364 inpatients affected by a major depressive episode treated with fluvoxamine, 300 mg/day ( n =266), or paroxetine, 20–40 mg/day ( n =98). The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression. Dopamine receptor D 2 (DRD2) and dopamine receptor D 4 (DRD4) allelic variants were determined in each subject by polymerase chain reaction. We observed that DRD2 and DRD4 variants were not associated with response to SSRI treatment. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, depressive symptoms at baseline, paroxetine and fluvoxamine plasma levels, and pindolol augmentation did not significantly influence the observed results. The investigated DRD2 and DRD4 gene variants therefore do not seem to play a major role in the antidepressant activity of SSRIs, at least in the present sample.

A Symptom-Specific Analysis of the Effect of High-Frequency Left or Low-Frequency Right Transcranial Magnetic Stimulation over the Dorsolateral Prefrontal Cortex in Major Depression

Background: We have investigated the efficacy of high-frequency left (HFL) versus low-frequency right (LFR) repetitive transcranial magnetic stimulation (rTMS) in depression, focusing on specific symptoms as possible predictors of outcome for these two different types of stimulation. Method: Seventy-four outpatients with a major depressive episode treated with an adequate antidepressant dosage for at least 4 weeks were included in our study and randomly assigned to two different groups: HFL or LFR rTMS. The Hamilton Rating Scale for Depression (HAM-D) items were pooled into 6 factors to evaluate specific symptoms as possible predictors of response. Results: Twenty-one out of 32 patients (65.6%) and 24 out of 42 patients (57.1%) were responders in the HFL and LFR groups, respectively. No significant difference in response rate was observed. Considering the whole sample, we found an inverse correlation between activity and HAM-D score reduction and a significant positive relation between somatic anxiety and outcome. An inverse correlation between psychic anxiety and HAM-D score reduction emerged considering the HFL group. In the LFR group, there was a significant negative relationship between baseline activity and the outcome. Conclusion: These findings support the hypothesis that LFR rTMS could be as effective as HFL rTMS and more suitable for patients with a higher anxiety degree, particularly in bipolar patients.