Linda Franchini

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.

How long should pindolol be associated with paroxetine to improve the antidepressant response

A double-blind study was undertaken to investigate the period of treatment with the beta-adrenoreceptor/5-hydroxytryptamine 1A (5-HT1A) antagonist pindolol required to enhance the antidepressant effects of paroxetine. After 1 week of a placebo run-in period, 63 untreated major depressive inpatients were randomly assigned to three different groups. Group 1 received paroxetine (20 mg/day) plus placebo (4 weeks). Group 2 received paroxetine (20 mg/day) plus pindolol (7.5 mg/day) for 1 week and placebo for 3 weeks. Group 3 received both active treatments for the entire duration of the study (4 weeks). Clinical response was defined as a reduction of the score in the Hamilton Rating Scale for Depression (HAM-D) to 8 or below. Also, to preliminarily examine whether beta-adrenoreceptor blockade was involved in the action of pindolol, another group of 10 inpatients was treated in an open-label manner with paroxetine (20 mg/day) plus 50 mg/day of the beta-adrenergic antagonist metoprolol, devoid of significant affinity for 5-HT1A receptors. At endpoint, the incidence of treatment-emergent side effects did not significantly differ among the three groups. After 1 and 2 weeks of treatment, the two groups treated with paroxetine plus pindolol displayed a significantly greater response rate than the group treated with paroxetine plus placebo. At study completion, only the patients treated with pindolol for the entire period showed a significantly greater response rate (p = 0.05). HAM-D score were also significantly lower at endpoint in patients treated with the combination for 4 weeks (p = 0.00003). The group of patients treated with paroxetine and metoprolol exhibited a side-effect profile comparable to that of paroxetine alone. Response rates were also comparable. These findings support the efficacy of pindolol, but not of metoprolol, in accelerating the antidepressant effect of paroxetine and suggest that the administration of pindolol for the entire period of the acute treatment may increase the efficacy of paroxetine.

Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees

Concordance to antidepressant response in members of the same family is a common observation in clinical practice. However, few published data support this view; moreover families with affected members responder to the same antidepressant have been poorly studied. We have analyzed 45 pairs consisting of one mood disorder fluvoxamine double-responder proband and one first-degree relative with known outcome to fluvoxamine treatment. Among 45 pairs 30 (67%) were concordant for good response to fluvoxamine. In family pedigrees of concordant pairs we found a significantly higher distribution of bipolar forms in secondary cases than in families of non concordant pairs (14.9% vs 3.9% P = 0.039) suggesting that concordance to antidepressant therapy could select families with higher genetic loading.

Dopamine receptor D2 and D4 genes, GABAA alpha-1 subunit gene and response to lithium prophylaxis in mood disorders

Lithium is an effective prophylactic agent in mood disorders, and genetic factors are likely to modulate individual susceptibility to lithium treatment. The aim of this study is to investigate the influence of dopamine receptor D2 (DRD2), D4 exon 3 (DRD4), and gamma-aminobutyric acid type A (GABA(A)) receptor alpha-1 subunit (GABRA1) gene variants on the efficacy of lithium prophylaxis in mood disorders. Patients with mood disorders (N = 125: bipolar subtype, n = 100; major depressive disorder subtype, n = 25) were followed prospectively for an average of 53 months and were typed for DRD2 (Ser311/Cys311: n = 121, VNTR: n = 63), DRD4 (n = 125) and GABRA1 (n = 61) variants using polymerase chain reaction (PCR) techniques. DRD2, DRD4 and GABRA1 variants were not associated with response to lithium. A trend was observed toward a better outcome of DRD4* 2/4 subjects, but it was due to only two subjects. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not reveal any association either. DRD2, DRD4 and GABRA1 variants therefore do not appear to be associated with the outcome of lithium prophylaxis in mood disorders.

A study of relapses in subjects with mood disorder on lithium treatment.

In a sample of 213 mood disorder subjects on long-term lithium treatment, we analyzed the recurrence indices of relapses during the prophylactic treatment period. The differences found in the recurrence rates were due to the current age and age of onset, duration of illness and polarity of the probands. The patients with personality disorders showed the worst relapse indices and could represent a group of mood disorder subjects with a bad outcome of lithium treatment.

Sertraline versus fluvoxamine in the treatment of elderly patients with major depression: a double-blind, randomized trial.

Background: Major depression is a common psychiatric disorder in the elderly population. The efficacy of tricyclic antidepressants is well established, and selective serotonin reuptake inhibitors appear to have a similar effectiveness along with advantages in terms of tolerability and safety. Given the lack of literature data regarding fluvoxamine in the treatment of depressed elderly patients, the aim of the present study was to compare its efficacy and tolerability with those of sertraline in a sample of elderly patients. Methods: Under double-blind conditions, 93 hospitalized patients older than 59 years, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a major depressive episode, were randomly assigned to receive sertraline (150 mg daily) or fluvoxamine (200 mg daily) for 7 weeks. The clinical response was defined as a reduction on the Hamilton Rating Scale for Depression score to 8 or below. Results: At study completion, the response rates were 55.6% (25/45) and 71.8% (28/39) for sertraline and fluvoxamine, respectively. No significant difference in final response rates was found between the 2 treatment groups (P = 0.12). A repeated-measures analysis of variance on Hamilton Rating Scale for Depression scores revealed a significantly different decrease of depressive symptoms between the 2 treatment groups, favoring fluvoxamine (P = 0.007). The overall safety profile of sertraline and fluvoxamine was favorable with no differences between the 2 drugs. Conclusion: The results of this double-blind trial show that sertraline and fluvoxamine may be effective compounds in the treatment of elderly depression with the latter showing some advantage in terms of speed of response. These findings warrant further replication in placebo-controlled studies.

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.

Patterns of symptom improvement during antidepressant treatment of delusional depression

We assessed the pattern of changes in depressive symptoms in delusional depressed inpatients treated openly with 300 mg/day of fluvoxamine for 6 weeks. We studied 59 inpatients affected by bipolar (n=23) and major depressive (n=36) disorders with psychotic features (DSM-IV) who showed complete responses to fluvoxamine treatment. Responses were evaluated using the Hamilton Rating Scale for Depression (HAMD-21, divided into: Core, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) administered at baseline and weekly until the 6th week. Random Regression Model (RRM) analysis was used to investigate the longitudinal time course of HAMD clusters. HAMD depressive symptom clusters decreased in a parallel manner from baseline to the end of the 6-week trial. The RRM analysis revealed no significant difference between HAMD clusters and the time course of the total HAMD score during treatment. Our data indicate that there is a simultaneous decrease in depressive symptoms during antidepressant treatment of delusional depressives.

Relapse during a 6-month continuation treatment with fluvoxamine in an Italian population: The role of clinical, psychosocial and genetic variables

The efficacy of SSRIs in relapse prevention in major depression has been extensively demonstrated. Considering published data, the relapse rate during a psychopharmacological continuation treatment ranges from 10% to 30%. Since the reasons of depressive relapses could be heterogeneous, we have tested the effect of clinical, psychosocial and genetic variables in sustained remission from an index depressive episode during continuation treatment with fluvoxamine over a 6-month follow-up period. 101 patients maintained the same full dosage treatment after remission from a depressive episode efficaciously treated with fluvoxamine. During the follow-up period, they were clinical assessed monthly by an experienced psychiatrist and SASS was administered, to assess their psychosocial adjustment. From a genetical point of view, SERTPR and CLOCK polymorphisms were analyzed for each patients, using PCR-based techniques. At the end of follow-up period, the 57.4% of the patients maintained remission during fluvoxamine continuation treatment; the 8.9% relapsed within the first 2 months of continuation; the 7.9% switched and the 25.8% dropped-out for poor compliance. Relapsed subjects presented a significantly longer mean duration of the index depressive episode than non-relapsed subjects and a subjective poor social adjustment than non-relapsed also in the euthymia period. None of the analyzed polymorphisms significantly appear to influence the outcome of the whole sample. The present data confirm that patients with severe depression and a long duration of the episode have a major risk of psychosocial disability. These patients could need a different psychopharmacological strategies and peculiar psychological intervention.

Migraine headache and mood disorders: a descriptive study in an outpatient psychiatric population

BACKGROUND Information is sparse concerning migraine distribution in mood disorder subjects based mainly on psychiatric disorder. METHODS In a sample of 283 normothymic mood disorder outpatients on maintenance treatment with serotonin reuptake inhibitors (SSRIs) or lithium, we investigated migraine distribution and clinical variables possibly related to comorbidity risk between mood disorder and migraine. RESULTS Some 26.8% of the sample met criteria for migraine with migraine age of onset earlier than mood disorder age of onset; familiarity for mood disorder and migraine was strictly related to comorbidity risk in probands. Long-term treatment with lithium salts subjectively improved migraine outcome. CONCLUSIONS These results could support the bidirectional association between the two clinical forms, considering the familial and pharmacological patterns.