Ricardo Alberto Moreno

Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: A double-blind placebo-controlled study

BACKGROUND Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cortex, and the treatment of depression is one of its potential therapeutic applications. Three recent meta analyses strongly suggest its benefits in the treatment of depression. The present study investigates whether repetitive TMS (rTMS) accelerates the onset of action and increases the therapeutic effects of amitriptyline. METHODS Forty-six outpatients meeting DSM-IV criteria for nonpsychotic depressive episode were randomly assigned to receive rTMS (n = 22) or sham repetitive TMS (sham) (n = 24) during 4 weeks over dorsolateral prefrontal cortex (DLPFC) in this double-blind controlled trial. All patients were concomitantly taking amitriptyline (mean dose 110 mg/d). The rTMS group received 20 sessions (5 sections per week) of 5 Hz rTMS (120% of motor threshold and 1250 pulses per session). Sham stimulation followed the same schedule, however, using a sham coil. The efficacy variables were the Hamilton Depression Rating Scale-17 items (HAM-D/17), the Montgomery-Asberg Depression Rating Scale (MADRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression (CGI). Tolerability was assessed by clinical examination and a safety screening of TMS side effects. RESULTS Repetitive TMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment (p < .001 compared with baseline and p < .001 compared with sham). The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth week). CONCLUSIONS Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline.

Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview

Dias VV, Balanzá‐Martinez V, Soeiro‐de‐Souza MG, Moreno RA, Figueira ML, Machado‐Vieira R, Vieta E. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview.

Comparison of the Effects of Mirtazapine and Fluoxetine in Severely Depressed Patients

AbstractIntroduction: Depression is a major global problem associated with large medical, sociological and economic burdens. Mirtazapine (Remeron®, Organon NV, The Netherlands) is an antidepressant with a unique mechanism of action that has similar or superior efficacy to TCAs and SSRIs in moderate-to-severe depression. However, this agent has not yet been tested in patients with severe depression alone. Objective: To compare the antidepressant efficacy and tolerability of mirtazapine and fluoxetine and their effects on anxiety and quality of life in patients with severe depression (≥25 points on the first 17 items of the Hamilton Depression Rating Scale [HDRS-17]). Methods: In this double-blind study, 297 severely depressed patients were randomised to receive mirtazapine 15–60 mg/day (n = 147) or fluoxetine 20–40 mg/day (n = 152) for 8 weeks. 294 subjects were actually treated and 292 included in the intent-to-treat population. Symptom severity was measured by the HDRS-17, Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) rating scale. Quality of life was self-assessed by patients using the Leeds Sleep Evaluation Questionnaire and the Quality of Life, Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study. Results: No statistically significant differences were noted between the two groups in change from baseline HDRS-17 score at any time point; both treatments were associated with large (∼15 points) decreases by study end. However, more mirtazapine-treated patients tended to exhibit a ≥50% decrease in HDRS score (significant at day 7; 9.0% vs 0.7%, p = 0.002). Significant differences in favour of mirtazapine were also observed at day 14 for changes in MADRS scores (−10.9 vs −8.5, p = 0.006) and the proportion of patients with ≥50% decrease in MADRS score (21.4% vs 10.9%, p = 0.031). On the CGI, the proportion of ‘much/very much improved’ patients tended to be greater with mirtazapine (significant at day 7; 9.7% vs 3.4%, p = 0.032). No significant between-group differences were observed for the majority of quality-of-life measures. However, mirtazapine produced significantly better improvements on ‘sleeping assessment 1’ (14.9 ± 5.2 vs 13.7 ± 5.4, p = 0.028) and ‘sleeping assessment 2’ (p = 0.013) than fluoxetine. Both agents were generally well tolerated but mirtazapine-treated patients experienced a mean weight gain of 0.8 ± 2.7kg compared with a mean decrease in weight of 0.4 ± 2.1kg for fluoxetine-treated patients (p < 0.001). Conclusions: Mirtazapine is as effective and well tolerated as fluoxetine in the treatment of patients with severe depression.

Hypomania : a transcultural perspective

This study examined the transcultural robustness of a screening instrument for hypomania, the Hypomania Checklist-32, first revised version (HCL-32 R1). It was carried out in 2606 patients from twelve countries in five geographic regions (Northern, Southern and Eastern Europe, South America and East Asia). In addition, GAMIAN Europe contributed data from its members. Exploratory and confirmatory factor analyses were used to examine the transregional stability of the measurement properties of the HCL-32 R1, including the influence of sex and age as covariates. Across cultures, a two-factor structure was confirmed: the first factor (F1) reflected the more positive aspects of hypomania (being more active, elated, self-confident, and cogni-tively enhanced); the second factor (F2) reflected the more negative aspects (being irritable, impulsive, careless, more substance use). The measurement properties of the HCL-32 R1 were largely invariant across cultures. Only few items showed transcultural differences in their relation to hypomania as measured by the test. F2 was higher among men and in more severe manic syndromes; F1 was highest in North and East Europe and lowest in South America. The scores decreased slightly with age. The frequency of the 32 items showed remarkable similarities across geographic areas, with two excep-tions: South Europeans had lower symptom frequencies in general and East Europeans higher rates of substance use. These findings support the interna-tional applicability of the HCL-32 R1 as a screening instrument for hypomania.

Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder.

Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.

Psicofarmacologia de antidepressivos

Antidepressant drugs turned depression into a treatable medical problem. In the last five decades, the psychopharmacology of depression has evolved rapidly. Early antidepressants - tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) - were discovered through clinical observation. The TCAs exhibited good antidepressant efficacy due to the enhancement in serotonin and norepinephrine availability. Its use was limited because of unwanted side effects and toxicity risk related to the blockade of histaminergic, cholinergic and alfa-adrenergic receptors. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with various medications and over-the-counter drugs. The new generation of antidepressants includes the single-receptor selective serotonin or norepinephrine inhibitors and the multiple-receptor-acting antidepressants, such as venlafaxine, bupropion, trazodone, nefazodone, and mirtazapine. They do not act on other receptor sites not related to depression (such as histamine or acetilcholine). This paper reviews the pharmacology of antidepressants, including its mechanism of action, pharmacokinetics, side effects and drug-drug interactions.

Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression: a randomized double-blind trial in a Brazilian sample

OBJETIVO: Hypericum perforatum demonstrou eficacia antidepressiva em comparacao ao placebo, mas comparacoes com outros antidepressivos permanecem controversas. Avaliamos a eficacia e a tolerabilidade do Hypericum perforatum em comparacao com fluoxetina e placebo, em um estudo duplo-cego de oito semanas em pacientes com depressao leve a moderada. METODO: Setenta e dois pacientes ambulatoriais receberam aleatoriamente doses fixas de Hypericum perforatum 900 mg/dia, fluoxetina 20 mg/dia ou placebo. Medidas de eficacia incluiram a HAM-D21, Escala de Montgomery-Asberg e Impressao Clinica Global. A seguranca foi avaliada por meio da Escala UKU de Efeitos Colaterais. RESULTADOS: A analise por intencao de tratar nao demonstrou diferencas entre os tres grupos. Na analise por casos observados, os pacientes que receberam Hypericum perforatum tiveram as menores taxas de remissao (12%, p = 0,016), em comparacao a fluoxetina (34,6%) e ao placebo (45%). CONCLUSOES: Hypericum perforatum foi menos eficaz que fluoxetina e placebo. Ambas as drogas foram seguras e bem toleradas. Estudos conclusivos com uma maior amostra sao necessarios.OBJECTIVE Hypericum perforatum has demonstrated antidepressant efficacy when compared to placebo, but comparisons with other antidepressants remain controversial. We assessed the efficacy and safety of Hypericum perforatum in comparison with fluoxetine, in a 8-week double-blind trial in patients with mild to moderate depression. METHOD Seventy-two outpatients were randomly assigned to receive Hypericum perforatum 900 mg/day, fluoxetine 20 mg/day or placebo. Efficacy measures included the HAM-D21 scale, the Montgomery-Asberg Rating Scale, and the Clinical Global Impression. Safety was assessed with the UKU Side Effect Rating Scale. RESULTS Intention-to-treat analysis showed no differences between the mean scores of the three groups. In the analyses of observed cases, patients receiving Hypericum perforatum had the lowest remission rates (12%, p = 0.016) compared to fluoxetine (34.6%) and placebo (45%). CONCLUSIONS Hypericum perforatum was less efficacious than both fluoxetine and placebo. Both drugs were safe and well-tolerated. Larger trials are needed for definite conclusions.

Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder

B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca2+) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using 1H-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type I and forty healthy controls aged 18–40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm3) 1H-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca2+, showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC.

Posture and body image in individuals with major depressive disorder: a controlled study.

OBJECTIVE In this study, we aimed to quantify posture and body image in patients with major depressive disorder during episodes and after drug treatment, comparing the results with those obtained for healthy volunteers. METHOD Over a 10-week period, we evaluated 34 individuals with depression and 37 healthy volunteers. Posture was assessed based on digital photos of the subjects; CorelDRAW software guidelines and body landmarks were employed. Body image was evaluated using the Body Shape Questionnaire. RESULTS During depressive episodes (in comparison with the post-treatment period), patients showed increased head flexion (p<0.001), increased thoracic kyphosis (p<0.001), a trend toward left pelvic retroversion (p=0.012) and abduction of the left scapula (p=0.046). During remission, patient posture was similar to that of the controls. At week 1 (during the episode), there were significant differences between the patients and the controls in terms of head flexion (p<0.001) and thoracic kyphosis (p<0.001); at weeks 8-10 (after treatment), such differences were seen only for shoulder position. The mean score on the Body Shape Questionnaire was 90.03 during the depressive episode, compared with 75.82 during remission (p=0.012) and 62.57 for the controls. CONCLUSION During episodes of depression, individuals with major depressive disorder experience changes in posture and mild dissatisfaction with body image. The findings demonstrate that the negative impact of depression includes emotional and physical factors.

Validation of the Portuguese version of the Social Adjustment Scale on Brazilian samples

BACKGROUND Social dysfunction is reported in several psychiatric diseases and its evaluation is becoming an important measure of treatment outcome. The aim of this study was to obtain normative data, to test the validity and the ability of the Portuguese version of the Self-Report Social Adjustment Scale (SAS-SR) to detect different clinical conditions. METHODS The Portuguese version of the SAS-SR was applied to a carefully selected non-psychiatric sample, and to depressed, panic, bulimic and cocaine-dependent patients. Depressed and panic patients were evaluated in two different clinical conditions: acutely symptomatic and in remission. RESULTS SAS overall and sub-scale scores of the normal sample were consistently lower than all patient groups, indicating better social adjustment in all areas. Panic patients were impaired to a lower level than depressed and cocaine-dependent patients in overall adjustment. Depressed patients in remission, although in better condition, were still impaired in relation to normal subjects in overall social functioning, leisure time and marital areas. In panic patients in remission, normalization was not achieved in overall functioning, work and marital areas. LIMITATIONS Sample size was small in some groups and the evaluation was cross-sectional. CONCLUSIONS The Portuguese version of SAS-SR is a useful instrument for detecting differences between psychiatric patients and normal subjects and for the evaluation of different clinical conditions, recommending its use in outcome studies.