Cristina Cusin

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.

A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression

BACKGROUND Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published. METHODS Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery-Åsberg Depression Rating Scale from baseline. RESULTS There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively. CONCLUSION The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed.

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.

Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders.

Disturbances of the serotoninergic neutrotransmitter system have been implicated in the pathogenesis of mood disorders. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with both unipolar and bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR might be associated with depressive symptomatology in a sample of mood disorder subjects. One hundred and thirty-two psychiatric inpatients affected by major depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR techniques. The only prior treatment permitted was low dose benzodiazepines (<5 mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic treatment was allowed. 5-httlpr variants were not associated with total depressive symptomatology as measured by hamd. the short 5-httlpr variant was marginally associated with higher psychic anxiety scores (f = 7.11, d.f. = 1,262, P = 0.008). The association was stronger among bipolars and early onset subjects. 5-HTTLPR variants were not associated with the remaining symptom clusters. The upstream regulatory region of the serotonin transporter gene has not, therefore, a major influence on the depressive symptomatology in mood disorder subjects.

Rating Scales for Depression

Over the past few decades, a number of clinician-rated and patient-rated instruments have been developed as primary efficacy measures in depression clinical trials. All those scales have relative strengths and weaknesses and some of them have been more successful than others, and have become the gold standards for depression clinical research. With all these measures available and with the evidence of their variable performance in clinical trials, it is becoming increasingly important to select primary efficacy measures that are reliable, valid, and that fit well within the aims of depression clinical trials. This article will review the main considerations that investigators need to make when choosing a primary efficacy measure for major depressive disorder (MDD). There is a clear need for a thorough discussion of the methodological issues concerning the use of these scales, as suggested also by Demyttenaere and De Fruyt in a recent review [1], because clinical trials researchers in depression continue to struggle with the ability to detect signals of the efficacy of antidepressant agents.

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.

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.

Treatment-Associated Suicidal Ideation and Adverse Effects in an Open, Multicenter Trial of Fluoxetine for Major Depressive Episodes

Background: Some reports suggest that a subset of depressed patients may experience suicidality – that is increase or emergence of suicidal ideation (SI) or behavior – after initiation of an antidepressant. The time course and clinical correlates of this phenomenon have not been characterized in detail. Method: We conducted a secondary analysis of a multicenter, prospective, open, 12-week trial of fluoxetine 20 mg in outpatients with nonpsychotic major depressive episodes. Adverse effects and other clinical features associated with the emergence of suicidality, defined using item 3 of the Hamilton Depression Rating Scale, were examined using Cox regression models. Results: Among 414 subjects without SI at baseline, 59 (14.3%) reported SI on at least 1 postbaseline visit. In a Cox regression, emergence of activation and worsening of depression severity were independently associated with emergence of SI, along with female gender, younger age and having thoughts that life was not worth living prior to treatment. Treatment response and remission were significantly less likely among subjects who developed SI. Conclusions: New SI was relatively common in this trial of fluoxetine and associated with the emergence of activation and overall symptomatic worsening. Whether prophylaxis against or aggressive treatment of adverse events can decrease emergence of SI merits further study.