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.

Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder.

BACKGROUND: Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects. METHODS: Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging. RESULTS: The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons. CONCLUSIONS: Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.

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.

Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression.

OBJECTIVE: In this study the authors evaluated the efficacy and the tolerability of sertraline and paroxetine in the treatment of delusional depression. METHOD: Under double-blind conditions, 46 hospitalized patients who met the DSM-III-R criteria for major depression with psychotic features were treated with sertraline or paroxetine for 6 weeks. RESULTS: The response rates were 75% and 46% for sertraline and paroxetine, respectively. The dropout rate was substantial (41%) in the paroxetine group and was attributable to side effects. CONCLUSIONS: Selective serotonin reuptake inhibitors administered alone are useful in the treatment of delusional depression.

Abnormalities of cAMP-dependent endogenous phosphorylation in platelets from patients with bipolar disorder.

OBJECTIVE: The aim of the study was to assess cAMP-dependent endogenous phosphorylation in platelets from euthymic bipolar patients. METHOD: Platelets from 10 drug-free euthymic patients with bipolar disorder were compared with those from 10 age- and sex-matched healthy subjects. Basal and cAMP-stimulated protein phosphorylation was examined in each group. RESULTS: Endogenous phosphorylation in both the healthy volunteers and the bipolar patients was significantly stimulated by cAMP; the major polypeptides had apparent molecular weights of 38 and 22 kDa. The cAMP-stimulated 32P incorporation differed between the bipolar patients and the comparison subjects only in the 22-kDa band. CONCLUSIONS: These data suggest a possible role of cAMP-dependent protein phosphorylation in the pathophysiology of bipolar disorder.

Fluvoxamine alone in the treatment of delusional depression.

OBJECTIVE: The aim of this study was to evaluate the efficacy of fluvoxamine in the treatment of delusional depression. METHOD: Fifty-nine inpatients who met the DSM-III-R criteria for major depression with psychotic features were treated with fluvoxamine for 6 weeks. Patients were assessed at baseline and weekly thereafter with the Hamilton Depression Rating Scale and the Dimensions of Delusional Experience rating scale. RESULTS: Of the 57 subjects completed the trial, 84.2% (N=48) recovered. The index episodes of the patients who did not respond to fluvoxamine were of significantly longer duration than those of the responders. CONCLUSIONS: Fluvoxamine has a response rate similar to that of the currently most efficacious treatments for delusional depression, including antidepressants plus antipsychotics and ECT.

Abnormal pattern of platelet APP isoforms in Alzheimer disease and Down syndrome.

OBJECTIVE: To determine if changes in levels of amyloid precursor protein (APP) isoforms in periphery are associated with Alzheimer disease and Down syndrome. DESIGN: After subjects were grouped according to diagnosis, APP isoform levels in platelets were compared. SETTING: University medical center. SUBJECTS: Ten patients who fulfilled diagnostic criteria for probable Alzheimer disease, 22 healthy volunteers, and 7 elderly (mean age, 42.7 years) and 7 young (mean age, 19.0 years) patients with Down syndrome. MAIN OUTCOME MEASURES: The levels of APP isoforms were evaluated by means of Western blot analysis and immunostaining of whole platelets. RESULTS: The ratio between the 130- and the 106- to 110-kd APP isoforms was markedly lower in patients with Alzheimer disease and in elderly patients with Down syndrome than in control subjects. In young patients with Down syndrome, the ratio did not significantly differ from that in control subjects. CONCLUSIONS: A consistent alteration in platelet APP isoforms has been found in Alzheimer disease and Down syndrome. Further studies will determine whether this alteration could provide a peripheral biochemical marker of the disorder and whether it could intervene in the pathogenesis of Alzheimer disease.

Effects of lithium on cAMP-dependent protein kinase in rat brain.

We have investigated the effects of lithium treatment on cAMP-dependent protein kinase in discrete brain areas of rat by using photoaffinity labeling as well as western blotting. Lithium administered for 5 weeks resulted in a significant increase of the cAMP binding to the 52 kDa cAMP-receptor in the soluble, but not in the particulate, fractions of both hippocampus and frontal cortex. Moreover, immunoblotting experiments revealed that chronic lithium treatment significantly increased the immunoreactivity against the regulatory and the catalytic subunits of the cAMP-dependent protein kinase in the soluble fraction of both brain areas. In contrast, no appreciable effect was observed in the particulate fractions. Short-term lithium treatment induced a significant increase in the immunolabeling of the catalytic subunits in the soluble fraction of both areas; whereas, the regulatory subunits and the actin were unchanged. In the particulate fractions, short-term lithium treatment did not elicit any substantial modification. Taken together, the results of the present study add to the growing evidence indicating that components of the cAMP signalling could play a crucial role in the biochemical action of lithium.

Two-year maintenance treatment with citalopram, 20 mg, in unipolar subjects with high recurrence rate.

BACKGROUND: The efficacy of citalopram, 20 to 60 mg/day, in relapse prevention in major depression was demonstrated in 6-month placebo-controlled studies. The authors tested the efficacy of citalopram, 40 mg/day, in relapse prevention over a 4-month period and citalopram, 20 mg/day, in recurrence prevention over a 24-month period. METHOD: Fifty inpatients with recurrent major depressive disorder (DSM-IV criteria) who had had at least one depressive episode during the 18 months preceding the index episode were openly treated with citalopram, 40 mg/day. Thirty-six subjects had a stable response to citalopram and remained in the continuation treatment with citalopram, 40 mg/day, for 4 months as outpatients. At the time of recovery, 32 patients gave their written informed consent before entering the 24-month maintenance period with citalopram, 20 mg/day. They were evaluated monthly by trained psychiatrists on the basis of the 21-item Hamilton Rating Scale for Depression. Every 3 months, patients were given the Sheehan Disability Scale, a self-rating instrument, to assess their psychosocial adjustment. RESULTS: No relapse was observed in the 4-month continuation period. Sixteen (50%) of 32 patients who entered the 24-month maintenance period had a new recurrence. Patients with recurrence showed a persistent moderate disability on Sheehan Disability Scale score, while no further differences were highlighted in clinical and demographic characteristics between patients with and without recurrence. CONCLUSION: In agreement with previous findings, these data suggest that a full dose of antidepressant is strongly recommended in prophylactic therapy of patients with recurrent major depression. Moreover, it appears that psychosocial impairment may increase the risk of recurrence, thus conditioning a poor outcome.

A double-blind study of long-term treatment with sertraline or fluvoxamine for prevention of highly recurrent unipolar depression.

BACKGROUND: We evaluated and compared the efficacy and safety of sertraline and fluvoxamine in a randomized, double-blind, parallel-group study during a follow-up of 24 months. METHOD: Sixty-four patients with recurrent, unipolar depression (DSM-IV criteria) who had at least one depressive episode during the 18 months preceding the index episode were accepted into the trial. Patients were randomly assigned to one of the two long-term treatment groups and evaluated monthly by trained psychiatrists, blinded to treatment option, on the basis of the Hamilton Rating Scale for Depression. RESULTS: All patients completed the 24-month follow-up period. Sertraline and fluvoxamine showed an equal efficacy in preventing new recurrences. In fact, there was no significant difference in survival rates between the two medication groups: 7 sertraline-treated patients (21.9%) and 6 fluvoxamine-treated patients (18.7%) had a single new recurrence (z = 0.14; p = .88). Moreover, recurrence observed during maintenance therapies was less severe and/or of shorter duration than index episodes. CONCLUSION: Long-term treatment with sertraline or fluvoxamine has been shown to be effective for prevention of highly recurrent unipolar depression. The high tolerability of these compounds, together with their prophylactic effectiveness, has an important role in improving the quality of life of these patients.

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.

Dose-response efficacy of paroxetine in preventing depressive recurrences: a randomized, double-blind study.

BACKGROUND: The authors evaluated and compared the efficacy of 20 mg versus 40 mg of paroxetine in a randomized, double-blind, parallel-group study during a maintenance period of 28 months. METHOD: Ninety-nine inpatients with recurrent, unipolar depression (DSM-IV criteria) who had at least 1 depressive episode during the 18 months preceding the index episode were openly treated with paroxetine 40 mg/day. Seventy-two subjects had a stable response (Hamilton Rating Scale for Depression score < 8) to paroxetine treatment and remained in the continuation treatment as outpatients for 4 months. At the time of recovery, 68 patients were randomly assigned to 1 of the 2 maintenance treatment groups: paroxetine 20 mg or paroxetine 40 mg daily. RESULTS: Sixty-seven patients completed the 28-month follow-up period. Seventeen (51.5%) of 33 patients in the 20-mg paroxetine regimen had a single recurrence compared with 8 (23.5%) of 34 subjects in the 40-mg dose regimen (chi2 = 5.56, p = .018). CONCLUSION: These data suggest that a full dose of paroxetine is recommended in unipolar patients who are at high risk for recurrent depressive episodes.

Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects.

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated 32P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder.

Worsening of delusional depression after sleep deprivation: case reports.

Five patients (three bipolars and two unipolars) affected by a major depressive episode with psychotic features were treated with total sleep deprivation (TSD) without concurrent psychotropic medication. After TSD we observed a worsening in psychotic as well as in depressive symptoms as rated on the Dimension of Delusional Experience Rating Scale and on Hamilton Rating Scale for Depression, respectively. TSD is known to markedly enhance the activity of brain monoaminergic pathways. Given the interaction between brain serotonergic and dopaminergic systems in delusional depression, it is possible that an enhancement in dopaminergic activity may be responsible of the symptomatological worsening in delusional depressives observed after TSD.

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.

cAMP-dependent phosphorylation system after short and long-term administration of moclobemide.

Accumulating evidence suggested that signal transduction cascade including protein phosphorylation is implicated in the neurochemical action of antidepressant agents. Clinical data indicated that moclobemide, a short acting and reversible inhibitor of monoamino oxidase type. A, is an effective antidepressant medication. However, little is known about the intracellular effects of this compound. Thus, in the present study we assessed the binding of cAMP to cAMP-dependent protein kinase (PKA) in rat cerebral cortex following short and long-term administration of moclobemide. The results showed that 21 days of treatment with moclobemide significantly increased the specific [32P]-cAMP covalent binding into the soluble 52-54 kDa cAMP-receptor. This effect was not seen following 1, 5 and 12 days of treatment. These findings suggest that PKA could be implicated in the biochemical effects of moclobemide.

Effects of fluvoxamine on the protein phosphorylation system associated with rat neuronal microtubules.

We have studied the phosphorylation system associated with the rat cerebrocortical microtubule fraction after short- and long-term administration (15 mg/kg) of fluvoxamine, a selective serotonin reuptake inhibitor with antidepressant activity. Fluvoxamine administered for 5 days significantly enhanced the 32P incorporation stimulated by cAMP into MAP2, while it failed to produce this effect after 12 and 21 days. Moreover, in the same periods of treatment no changes were observed in basal phosphorylation and in the pattern of microtubule proteins. In conclusion, our results suggest that changes in the protein phosphorylation system associated with the microtubule fraction could represent an early neurochemical modification involved in the action of fluvoxamine.

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.