Biomedical subjects

E Smeraldi

Publications and source records attributed to E Smeraldi.

At least 19 recordsLinked to original sources

PubMed2002

Serotonin transporter gene (5-HTTLPR) and major psychoses.

Serotoninergic neurotransmitter systems have been implicated in the pathogenesis of major psychoses. A functional polymorphism (5-HTTLPR) in the upstream regulatory region of the gene (SLC6A4) has been associated with a number of psychiatric disturbances, but conflicting replication followed. The aim of this study was to investigate the possibility that the 5-HTTLPR might be associated with major psychoses. One thousand, eight hundred and twenty inpatients (789 bipolars, 667 major depressives, 66 delusionals, 261 schizophrenics, 37 psychotics not otherwise specified-NOS) and 457 control subjects were included in this study. A subsample of 1235 patients (523 bipolars, 359 major depressives, 259 schizophrenics, 66 delusionals, 28 psychotic NOS) were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic illness (OPCRIT) checklist. The subjects were also typed for 5-HTTLPR variants using PCR techniques. 5-HTTLPR allele frequencies were not significantly different between controls and bipolars, major depressives, schizophrenics, delusionals and psychotic NOS; genotype analysis also did not show any association. The analysis of symptomatology did not show significant differences. Consideration of possible stratification factors such as sex and age of onset did not significantly influence results. 5-HTTLPR variants are not therefore a liability factor for major psychoses or for major psychoses symptomatology.

Adult↗

PubMed2002

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD.

Alleles↗

PubMed2002

cAMP signaling pathway in depressed patients with psychotic features.

Abnormalities in protein kinase A (PKA) and Rap1 have recently been reported in depressed patients. The aim of the present study was to investigate the levels of these proteins in platelets from untreated unipolar and bipolar depressed patients with psychotic features. The levels PKA and Rap1 were assessed by Western blot analysis and immunostaining in 37 drug-free patients and 29 healthy subjects. Both unipolar and bipolar patients with psychotic depression have significantly lower levels of platelet regulatory type I and higher levels of catalytic subunits of PKA than controls, whereas the levels of regulatory type II were higher only in psychotic unipolar patients. No significant differences were found in the immunolabeling of both Rap1 and actin among groups. These findings support the idea that besides nonpsychotic depression, abnormalities of PKA could be linked, albeit in a somewhat different way, with psychotic depression.

Adult↗

PubMed2001

Long-term treatment with citalopram in patients with highly recurrent forms of unipolar depression.

The authors evaluated the efficacy and safety of citalopram in a 28-month study in 48 inpatients with highly recurrent forms of unipolar depression. The patients, who each had at least one depressive episode during the 18 months preceding the index episode, were openly treated with citalopram, 40 mg/day. Thirty-six of the patients had a stable response to citalopram and continued treatment as outpatients for 4 months. No relapses were observed. At the time of recovery, 32/36 subjects received maintenance treatment with citalopram (40 mg) for an additional 24 months. At the end of the study, 11/32 patients experienced a single new recurrence.

Adult↗

PubMed2001

No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors.

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.

Major Depressive Disorder↗

PubMed2001

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 patient's genetic 5-HTTLPR pattern.

Adult↗

PubMed2001

Tryptophan hydroxylase gene and major psychoses.

Disturbances of the serotoninergic neurotransmitter system have been implicated in the pathogenesis of mood disorders. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, has been recently reported to be associated with bipolar disorder. In this study, we investigated TPH A218C gene variants in a sample of subjects affected by major psychoses. One thousand four hundred and twenty-four inpatients affected by bipolar (n=627), major depressive (n=511), schizophrenic (n=210), delusional (n=48) disorder and psychotic disorder not otherwise specified (n=27) (DSM-IV) were included; all patients and 380 controls were typed for the TPH variants using PCR techniques. A sub-sample of 963 patients was assessed using the Operational Criteria for Psychotic Illness (OPCRIT). TPH variants were not associated with major psychoses, but a trend was observed toward an excess of TPH*A/A in bipolar disorder. The analysis of symptomatology factors did not show any significant difference either; however, a trend was observed for males with the TPH*A genotype to have lower depressive symptoms compared with TPH*C subjects. Possible stratification factors such as current age and age of onset did not affect the observed results. TPH A218C variants are not, therefore, a major liability factor for the symptoms of major psychoses to have in the present sample. TPH*A containing variants may be a protective factor for depressive symptoms among male subjects with mood disorders or for a subtype of mood disorders characterized by a mainly manic form of symptomatology.

Adult↗

PubMed2001

DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects.

We previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample of 1,264 patients were evaluated using the OPCRIT checklist and differences of symptomatology factor scores among genetic variants were assessed using one-way analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars, schizophrenics, delusionals, and psychotic NOS were not significantly different from controls; major depressives showed a trend toward an excess of DRD4*Short and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the whole subsample of 1,264 subjects showed a significant difference on delusion factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long containing variants associated with severe symptomatology. The analysis in the replication subjects only (n = 803) showed a trend in the same direction, though not reaching the significance level. This analysis in an enlarged sample suggests that DRD4*Long alleles exert a small but significant influence on the delusional symptomatology in subjects affected by major psychoses.

Adult↗

PubMed2001

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

Alleles↗

PubMed2001

Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder.

BACKGROUND: Panic attacks can be induced in persons with panic disorder by inhalation of carbon dioxide. Hypercapnia also elicits a reflex hyperventilation, which is controlled in part by cholinergic mechanisms. This study investigated whether the exaggerated response to carbon dioxide in panic disorder (PD) can be modulated by antagonists of muscarinic cholinergic receptors. METHODS: Twelve patients with PD received biperiden hydrochloride (a muscarinic antagonist that crosses the blood-brain barrier), pirenzepine hydrochloride (a muscarinic antagonist that does not cross the blood-brain barrier), or placebo 2 hours before a 35% carbon dioxide-65% oxygen respiratory challenge (vs air as a placebo) on 3 separate days, in a double-blind, random crossover design. RESULTS: According to patients' self-ratings of subjective anxiety, inhalation of the carbon dioxide/oxygen mixture provoked a significant and intense response after treatment with pirenzepine and placebo. After biperiden treatment, however, hypercapnia elicited a response profile similar to that elicited by air, whereby subjective anxiety remained similar to preinhalation levels. CONCLUSIONS: Consistent with the hypothesis of the study, a centrally active muscarinic antagonist can block the response to carbon dioxide commonly observed in subjects with PD.

Adult↗

PubMed2001

Major psychoses symptomatology: factor analysis of 2241 psychotic subjects.

Current nosography classifies major psychoses as separate disorders, but their symptomatological presentation during illness episodes largely overlaps and diagnoses may change during a lifetime. Few analyses of major psychoses symptomatology have been performed so far because of the large number of subjects needed to obtain stable factors. The purpose of this study was, therefore, to identify the symptomatologic structure common to major psychoses based on lifetime symptoms. Two thousand and forty-one inpatients affected by schizophrenic (n=1008), bipolar (n=563), major depressive (n=352), delusional (n=108) and psychotic not otherwise specified disorder (n=210) were rated for lifetime symptoms using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and included in a factorial analysis. Four factors were obtained, the first consisted of excitement symptoms, the second comprised psychotic features (delusions and hallucinations), the third comprised depression and the fourth disorganization. When scored by the OPCRIT checklist, major psychoses symptomatology is composed of excitement, depressive, delusion and disorganization symptoms.

Adult↗

PubMed2001

Morning sunlight reduces length of hospitalization in bipolar depression.

BACKGROUND: Bright artificial light improves non-seasonal depression. Preliminary observations suggest that sunlight could share this effect. METHODS: Length of hospitalization was recorded for a sample of 415 unipolar and 187 bipolar depressed inpatients, assigned to rooms with eastern (E) or western (W) windows. RESULTS: Bipolar inpatients in E rooms (exposed to direct sunlight in the morning) had a mean 3.67-day shorter hospital stay than patients in W rooms. No effect was found in unipolar inpatients. CONCLUSIONS: Natural sunlight can be an underestimated and uncontrolled light therapy for bipolar depression. LIMITATIONS: This is a naturalistic retrospective observation, which needs to be confirmed by prospective studies.

Adult↗

PubMed2001

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.

Antidepressive Agents, Second-Generation↗

PubMed2001

A neural network approach to the outcome definition on first treatment with sertraline in a psychiatric population.

Therapy decision is one of the most important tasks clinicians have to perform in their clinical practice. The decision process requires taking into account many different factors. The Authors have proposed a neural computing approach for supporting clinical decision analysis. The mathematical model of artificial neural network (ANN) has been applied on a pool of clinical information gathered through case description freely filled by senior psychiatrists into 416 clinical charts. Sertraline, as drug for treatment, has been chosen since its clinical uses range from treatment of depression to that of many other psychiatric clinical conditions so that it has been thought to be a good candidate to this type of study. The ANN performance in forecasting successful and unsuccessful treatment cases showed an overall accuracy of classification of 97.35%. This result suggests a possible future application of this method to obtain a reliable prediction of a given psychiatric patient outcome during a specific psychopharmacological therapy, optimising the decisional making process.

Adolescent↗

PubMed2001

Protein kinase A and Rap1 levels in platelets of untreated patients with major depression.

We have recently reported altered levels of protein kinase A and Rap1 in patients with bipolar disorder. The purpose of the current investigation was to assess the levels of these proteins in platelets from untreated euthymic and depressed patients with major unipolar depression. Platelets were collected from 45 drug-free unipolar patients (13 euthymic and 32 depressed) and 45 healthy subjects. The levels of protein kinase A and Rap1 were assessed by Western blot analysis, immunostaining and computer-assisted imaging. The immunolabeling of the regulatory subunit type II of protein kinase A and that of Rap1 was significantly lower in untreated depressed patients compared with untreated euthymic patients and healthy subjects. No significant differences were found in the immunolabeling of both the regulatory type I and the catalytic subunits of protein kinase A among groups. Levels of the regulatory subunit type II of protein kinase A and Rap1 are altered in platelets of unipolar depressive patients. These findings may provide new insight about the relationship between components of cAMP signaling and affective disorders.

Adult↗

PubMed2001

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 patient's therapy according to their genetic pattern.

Adult↗

PubMed2001

Serotonin transporter gene associated with lithium prophylaxis in mood disorders.

The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques. 5-HTTLPR variants were associated with lithium outcome (F = 5.35; df = 2,198; P = 0.005). Subjects with the s/s variant showed a worse response compared to both l/s and l/l variants. Consideration of possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment and previous episodes did not influence the observed association. 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders.

Adult↗

PubMed2001

A comparison of citalopram and paroxetine in the treatment of panic disorder: a randomized, single-blind study.

BACKGROUND: Serotonin Selective Re-uptake Inhibitors (SSRIs) are the drugs of choice for treating panic disorder (PD). In vitro studies have shown different pharmacodynamic profiles for SSRIs, but their clinical relevance is still unknown. Paroxetine, the SSRI with the strongest serotonergic effect, also shows significant cholinergic and noradrenergic activities. In this class of drugs, citalopram is the most selective for serotonin. We compared these two drugs and their effectiveness and tolerability in a sample of patients with PD in a two-month treatment course. METHOD: Fifty-eight patients with PD were randomly assigned to either the paroxetine or the citalopram treatment group in a single-blind, randomized design. Each patient was assessed at days 0, 7 and 60 by the Panic Associated Symptoms Scale (PASS), the Sheehan Disability Scale (SDS) and the Fear Questionnaire (FQ). Primary outcome measures were the percentage of patients free of panic attacks, anticipatory anxiety and phobic avoidance in the last week of the trial and the percentage of good responders, as defined by a reduction of at least 50% from baseline of both PASS and SDS global scores at day 60. RESULTS: At day 60, 86% of patients receiving citalopram and 84% of those receiving paroxetine responded well to treatment. No significant differences between the two drugs were found. Both were well tolerated, although sexual side effects and weight gain were frequent. Anticipatory anxiety decreased significantly after the first week of treatment, and no initial worsening in the panic attacks was observed. CONCLUSION: Paroxetine and citalopram show similar anti-panic properties and a good tolerability profile. Our results support evidence that the serotonergic system plays a significant role in the anti-panic properties of these two SSRIs.

Adult↗