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.

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.

A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia.

AIM: Evaluation of the effect of acetyl-L-carnitine (ALCAR) vs. amisulpride measured by total Hamilton Depression Rating Scale score (HAM-D(21)) in patients with pure dysthymia (DSM IV). Two hundred and four patients were randomised and treated with ALCAR 500 mg b.i.d. or amisulpride 50 mg u.i.d. in a double-blind study, for 12 weeks. RESULTS: A solid improvement of HAM-D(21) was observed in both treatment groups throughout the study. The results did not disclose statistically significant differences between treatments, although the confidence interval for the non-inferiority of the primary end-point exceeded the pre-established limit of 2 by 0.46 points. According to a non-inferiority margin of 3 (considered acceptable by recent published data) the primary end-point could have been fully satisfied. CDRS, MADRS and CGI, employed to further measure the clinical outcome, reported similar results in both treatment groups. The greater tolerability of ALCAR is of clinical relevance considering the chronicity of dysthymia, which often requires prolonged treatment.

Staging of pelvic endometriosis based on MRI findings versus laparoscopic classification according to the American Fertility Society.

BACKGROUND: Preoperative staging of pelvic endometriosis helps the gynecologist plan therapy and offers a prognosis to patients. We compared a staging system of pelvic endometriosis based on magnetic resonance imaging (MRI) findings with the American Fertility Society (AFS) laparoscopic classification. METHODS: Forty-four consecutive females with clinically suspected endometriosis underwent MRI examination to demonstrate the presence of endometriomas and pelvic implants. Laparoscopy was performed within 2 weeks. An MRI score was developed to classify endometriosis into four classes comparable to those of AFS laparoscopic staging. Concordance between MRI and laparoscopic classification was evaluated with kappa statistics. RESULTS: Laparoscopy confirmed 60 of 61 endometriomas detected by MRI. Implants were discovered in 20 of 44 patients with MRI and in 23 of 44 with laparoscopy. MRI detected 50 endometrial implants of 65 detected by laparoscopy (76.9%). With regard to endometriosis staging, we obtained a concordance between MRI and AFS classification in 42 of 44 patients (kappa = 0.913). CONCLUSION: Although MRI has limitations such as suboptimal depiction of small implants and adhesions, this technique is very useful to guide laparoscopy. Moreover, the optimal concordance (95%) between our proposed MRI staging and the AFS laparoscopic classification demonstrated a new advantage of MRI in preoperative staging of endometriosis.

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.

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.

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.

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.

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.

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.

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.

Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study.

The changes in aminergic receptors elicited by antidepressant treatments have been extensively examined in the brain of experimental animals using radioligand and molecular techniques. However, there is a very limited direct information regarding the changes effected by such treatments in the human brain, as well as its relationship to clinical improvement. Using positron emission tomography (PET) scanning, the authors examined the cortical 5-Hydroxytryptamine-2A (5-HT2A) receptor binding of [18F]fluoro-ethyl-spiperone after a 4-week treatment with the selective serotonin reuptake inhibitor paroxetine. [18F]fluoro-ethyl-spiperone labels 5-HT2A receptors in the cortex and dopamine D2 receptors in the basal ganglia. A binding index (BI) was calculated in the frontal cortex and the basal ganglia (mostly caudate-putamen) by reference to cerebellum. Thirty-seven inpatients with major depression with a mean +/- SD score on the 21-item Hamilton Rating Scale for Depression (HAM-D-21) of 26.3 +/- 4.3 at admission were treated with paroxetine 40 mg/day. After 4 weeks of treatment, the BI in the frontal cortex of remitted patients (HAM-D-21 score = 4.7 +/- 4.0; N = 20) was significantly greater than the score in nonresponder patients (HAM-D-21 score = 21.2 +/- 4.0; N = 17) (BI = 0.54 +/- 0.15 and 0.41 +/- 0.17, respectively; p < 0.02). No such difference was observed in the basal ganglia (5.45 +/- 1.11 and 5.39 +/- 0.82, respectively; p = 0.85). The significant difference in cortical BI persisted when age was used as covariate (p < 0.016). These data suggest that clinical improvement in patients treated with paroxetine is associated with an increase in the density of 5-HT2A receptors in the frontal cortex.

Will a second prophylactic treatment with a higher dosage of the same antidepressant either prevent or delay new depressive episodes?

Fifty-seven highly recurrent unipolar patients, excluded from previous long-term studies with selective serotonin reuptake inhibitors (SSRIs) after they experienced a new recurrence, were acutely treated with the full dosage of the SSRIs they were on. Fifty-one of them (89.5%) had a sustained response and entered into the 4-month continuation therapy. During this phase, no relapse was observed. At the end of it, all patients gave their written informed consent to be enrolled in a 24-month long-term therapy, maintaining the same treatment dosage of fluvoxamine 300 mg/day, sertraline 150 mg/day, or paroxetine 40 mg/day. At the end of the study, 28 out of the 51 outpatients (54.9%) showed a further recurrence. Nevertheless, second recurrences observed during this second maintenance therapy were less severe than first recurrences, decreasing from 25.1+/-3.4 to 21.6+/-3.3 (P<0.0001), respectively. Considering the clinical characteristics of patients, we found that a high number of prior depressive episodes and an early age at onset of illness may predict a bad outcome. Moreover, patients with a longer duration of euthymia during a first maintenance period are less likely to have a new episode of depression.

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.

Four-year follow-up study of sertraline and fluvoxamine in long-term treatment of unipolar subjects with high recurrence rate.

We prolonged from 24 to 48 months a follow-up study of unipolar subjects with high recurrence rate treated with fluvoxamine (N=25) and sertraline (N=22). During the two-year additional period a significant risk of recurrences was observed during the third year of follow-up, without differences in the two long-term therapy groups. During the fourth year no patients showed new episodes of illness.

Altered Rap1 endogenous phosphorylation and levels in platelets from patients with bipolar disorder.

Previous studies have reported abnormalities either in the cAMP-dependent endogenous phosphorylation or in the levels of Rap1 in platelets from bipolar patients. One limitation of these findings was that they come from different groups of patients in independent studies. To overcome this limitation, we designed the present study in which both these biochemicals parameters were assessed in the same cohort of euthymic bipolar patients and healthy subjects. The results showed that the cAMP-dependent phosphorylation of Rap1 was significantly higher in platelets of bipolar patients with respect to healthy subjects. Furthermore, immunoblotting experiments revealed that also the levels of Rap1 were significantly higher in bipolar patients than in control subjects, thus supporting that the abnormal phosphorylation can be ascribed to the increased levels of Rap1. Taken together the results of the present study further support that downstream components of the cAMP signal cascade could be involved in the pathophysiology of bipolar disorders.

Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study.

BACKGROUND: Previous studies have reported the efficacy of selective serotonin reuptake inhibitors as monotherapy in the treatment of delusional depression. The clinical efficacy of venlafaxine, a serotonin-norepinephrine reuptake blocker, has been demonstrated in the treatment of patients with moderate-to-severe depression, but, to date, no evidence is available about its use in depressed patients with psychotic features. METHOD: Under double-blind conditions, 28 hospitalized patients who met DSM-IV criteria for major depression, severe with psychotic features, were randomly assigned to receive fluvoxamine or venlafaxine, 300 mg/day, for 6 weeks. Severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D) and the Dimensions of Delusional Experience Rating Scale (DDERS) administered at baseline and every week thereafter. Side effects were also recorded. Clinical response was defined as a reduction of the scores in the 21-item HAM-D to 8 or below and in the DDERS to 0. RESULTS: At study completion, the response rates were 78.6% (N = 11) and 58.3% (N = 7) for fluvoxamine and venlafaxine, respectively. No significant difference was found between drugs (Fisher exact test, p = .40). Analysis of covariance on HAM-D scores did not reveal a significantly different decrease of depressive symptomatology between the 2 treatment groups (p = .14). Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded. The overall safety profile of both fluvoxamine and venlafaxine was favorable. CONCLUSION: The results of this pilot double-blind trial show that fluvoxamine is useful in the treatment of delusional depression and suggest that venlafaxine may also be an effective compound in the treatment of this disorder. The latter finding, although promising, warrants further replication in a larger sample of patients.

Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment.

OBJECTIVE: During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders. METHODS: Among the components of cAMP signaling, this review focuses on the cAMP-dependent phosphorylation system. We analyzed the basic components of the cAMP-dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP-dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed. RESULTS: The studies herein presented demonstrated that the levels and the activity of cAMP-dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore. these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP-dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP-dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders. CONCLUSIONS: Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.

Early onset of lithium prophylaxis as a predictor of good long-term outcome.

The recurrence rates during lithium preventive treatment were investigated in a sample of 270 Mood Disorder subjects subdivided according to their onset time for lithium prophylaxis as very early (within 5 years from the onset of illness), early (6-10 years), late (11-20 years) and very late (more than 21 years). 131 subjects of the sample followed for 4 years prolonged the observation for a further period of 8 years. Results indicated that beginning lithium therapy within the first ten years of illness predicts better preventive outcomes than beginning prophylaxis later, both in major depression, recurrent and bipolar patients.