A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention.

BACKGROUND: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. METHODS: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. RESULTS: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. LIMITATIONS: The small sample size limited the statistical power and external validity. CONCLUSION: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. TRIAL REGISTRATION: NCT01268137 (ClinicalTrials.gov).

Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: an exploratory study.

Deep brain stimulation (DBS) is being investigated as a therapeutic alternative for patients with treatment-resistant depression (TRD), but its cognitive safety has been scarcely explored. The aim of this exploratory study is to evaluate cognitive function of patients before and after deep brain stimulation of the subgenual cingulate gyrus (SCG). Eight treatment-resistant depressed patients were implanted in subgenual cingulate gyrus. A neuropsychological battery was used to evaluate patients before surgery and 1-year after. A matched group of eight first-episode patients was also assessed. A MANOVA was performed for each cognitive domain and those tests showing main time effects were then correlated with depressive symptoms and with medication load. There were significant group and time effects for memory and a group effect for language. No significant interactions between groups or cognitive domains were observed. Medication load was negatively correlated with memory at time 1, and clinical change negatively correlated with memory improvement. These findings support the cognitive safety of DBS of subgenual cingulate gyrus, as cognitive function did not worsen after chronic stimulation and memory performance even improved. The results, though, should be interpreted cautiously given the small sample size and the fact that some treatment-resistant patients received electroconvulsive therapy (ECT) before implantation.

Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression.

BACKGROUND: Positron emission tomography (PET) studies have shown that the antidepressant effect of chronic deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may be consequence of modifications of brain metabolism at key structures involved in depression. Like clinical benefits, these metabolic changes may reverse when the stimulation is discontinued, even preceding clinical worsening. However no data on immediate effects of DBS discontinuation are available. The aim of this study was to determine immediate cerebral metabolism changes during a short switch-off of electrical stimulation in implanted patients with treatment-resistant depression (TRD) who had achieved clinical improvement after a period of chronic DBS. METHODS: Seven patients with TRD who had been previously implanted for DBS in SCG were included. After a period of clinical stabilization two consecutive FDG-PET were acquired, the first with active stimulation and the second after 48 h of inactive stimulation. A HAMD-17 to assess depressive symptoms was performed before both scans. Analyses were performed with SnPM8. RESULTS: Inactive stimulation was characterized by metabolism decreases in dorsal anterior cingulate (Broadmann Area, BA24), premotor region (BA6) and putamen with respect to active stimulation. No clinical changes according to HAMD-17 were detected. LIMITATIONS: The main limitation of this study is the small sample size. CONCLUSION: Our results point to immediate effects of DBS discontinuation on metabolism of brain depressive network which precede clinical changes, helping to disentangle the rationale behind DBS efficacy in TRD.

Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden.

BACKGROUND: Smaller hippocampal volumes in major depressive disorder (MDD) have been linked with earlier onset, previous recurrences and treatment refractoriness. The aim of our study was to investigate metabolite abnormalities in the hippocampus associated with past depressive illness burden. METHODS: Glutamate/glutamine (Glx), N-acetylaspartate (NAA) and choline (Cho), potential markers of glial/neuronal integrity and membrane turnover, respectively, were measured in adults with depression and healthy controls using a 3 T magnetic resonance spectroscopy scanner. Voxels were placed in the head of the right and left hippocampus. We controlled for systematic differences resulting from volume-of-interest (VOI) tissue composition and total hippocampal volume. RESULTS: Our final sample comprised a total of 16 healthy controls and 52 adult patients with depression in different stages of the illness (20 treatment-resistant/chronic, 18 remitted-recurrent and 14 first-episode), comparable for age and sex distribution. Patients with treatment-resistant/chronic and remitted-recurrent depression had significantly lower levels of Glx and NAA than controls, especially in the right hippocampal region (p ≤ 0.025). Diminished levels of Glx were correlated with longer illness duration (left VOI r = -0.34, p = 0.01). By contrast, Cho levels were significantly higher in patients with treatment-resistant/chronic depression than those with first-episode depression or controls in the right and left hippocampus (up to 19% higher; all p ≤ 0.025) and were consistently related to longer illness duration (right VOI r = 0.30, p = 0.028; left VOI r = 0.38, p = 0.004) and more previous episodes (right VOI r = 0.46, p = 0.001; left VOI r = 0.44, p = 0.001). LIMITATIONS: The cross-sectional design and the inclusion of treated patients are the main limitations of the study. CONCLUSION: Our results support that metabolite alterations within the hippocampus are more pronounced in patients with a clinical evolution characterized by recurrences and/or chronicity and add further evidence to the potential deleterious effects of stress and depression on this region.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression.

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-µs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Ventromedial prefrontal spectroscopic abnormalities over the course of depression: a comparison among first episode, remitted recurrent and chronic patients.

Structural and neuropathological alterations in the ventromedial prefrontal cortex (vmPFC) described in depression (MDD) might become even more pronounced over the course of illness. Measurement of brain metabolites by means of Magnetic Resonance spectroscopy (MRS) can indirectly deliver information about glial and neuronal integrity or potential cellular loss. The aim of this study was to investigate whether Glutamate (Glu), Choline (Cho) and total N-acetylaspartate (total-NAA) levels in the vmPFC differed among MDD patients in distinct stages of illness and healthy controls. We hypothesized that high-past illness-burden would represent more metabolite abnormalities independently of mood state. A 3-Tesla MR facility was used to measure these metabolites in vmPFC of 45 depressive patients (10 first-episode-MDD, 16 remitted-recurrent-MDD and 19 chronic-MDD) and 15 healthy controls. Multivariate and correlation analyses were carried out to explore the influence of duration of illness, age at onset and mood-state. Levels of Glu were significantly decreased in remitted-recurrent and chronic patients compared with both first-episode and controls (up to 28% mean reduction; p < 0.001, Cohen's d = 2.88) and were negatively correlated with illness duration (r = -0.56; p < 0.001). Cho levels showed an opposite pattern: highest values were detected in chronic patients, correlating positively with duration of illness (r = 0.32; p = 0.03). Total-NAA levels were significantly lowered in remitted-recurrent and chronic patients, which were associated with an earlier age at onset (r = 0.50; p = 0.001). Our data suggest that abnormalities in Glu, Cho and total-NAA levels are consistently related to the course of MDD, supporting the hypothesis that cellular changes would take place in vmPFC over time.

Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.

Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3' near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

A short duration of untreated illness (DUI) improves response outcomes in first-depressive episodes.

BACKGROUND: Few studies have addressed the implication of the duration of untreated illness (DUI) on the clinical outcome of mood disorders. Although not focusing on DUI, previous findings suggest that the longer it takes to start appropriate treatment, the worse will be the evolution of depressive disorder. We sought to determine the effect of the duration of untreated episode (DUE) on 1) rates of response to treatment, 2) time to attain a sustained response and 3) rates of remission of MDD, dealing specially with first-depressive episodes. METHODS: 141 patients with MDD were grouped into long DUE (>8 weeks) and short DUE (< or =8). Statistical analyses were performed to determine differences in outcome variables. The same analyses were repeated by splitting the sample between first-episode and recurrent depression. RESULTS: The percentage of patients who achieved a sustained response was significantly higher in the group with a short DUE [OR=2.6; 95% CI 1.3-5.1]. Survival analyses showed that patients with a long DUE delayed longer time to attain a sustained response [39 vs. 20 days, p=0.012]. Once the sample was split, these results were even more pronounced in the subsample of first-depressive episode patients. LIMITATIONS: Given that the sample was originally recruited for two clinical trials, the follow-up period of this study is only six weeks long. CONCLUSIONS: Our results indicate that response to antidepressant treatments is faster when the no-treatment interval is reduced. The earliest treatment of first-depressive episodes seems to be crucial since a shorter duration of untreated illness implies better response outcomes.

Pindolol augmentation enhances response outcomes in first depressive episodes.

Effectiveness of Pindolol addition to SSRIs is still a matter of debate. Recently, Geretsegger et al. [Geretsegger, C., Bitterlich, W., Stelzig, R., Stuppaeck, C., Bondy, B. and Aichhorn, W. (2008) Paroxetine with Pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. Eur. Neuropsychopharmacol. 18, 141-146.] have found that never-medicated depressed patients showed a significant sustained response with Paroxetine + Pindolol treatment. Also, patients with a first depressive episode displayed a trend for higher sustained response rates with Pindolol co-administration. Re-analysing the data of a previous clinical trial of Fluoxetine + Pindolol [Pérez, V., Gilaberte, I., Faries, D., Alvarez, E. and Artigas, F. (1997). Randomised, double-blind, placebo-controlled trial of Pindolol in combination with Fluoxetine antidepressant treatment. Lancet 349, 1594-1597.], we have found that first depressive episodes are associated with a significant higher percentage of sustained responses when administering Fluoxetine + Pindolol (70.3%) compared to Fluoxetine + Placebo (44%). Moreover, based on a survival analysis, among the patients with a first depressive episode, those who received Fluoxetine + Pindolol achieved a sustained response significantly earlier (19 days) than those on Fluoxetine + Placebo (35 days). Interestingly, none of these effects were observed in the subsample of recurrent patients. The results suggest that Pindolol augmentation accelerates and enhances the action of SSRI at the beginning of the illness.

Ziprasidone in the treatment of borderline personality disorder: a double-blind, placebo-controlled, randomized study.

OBJECTIVE: The aim of this double-blind, placebo-controlled study was to evaluate the efficacy and tolerability of ziprasidone in the treatment of adult patients with borderline personality disorder. METHOD: Sixty DSM-IV borderline personality disorder patients were included from March 2004 to April 2006 in a 12-week, single-center, double-blind, placebo-controlled study. The subjects were randomly assigned to ziprasidone or placebo in a 1:1 ratio following a 2-week baseline period. The Clinical Global Impressions scale for use in borderline personality disorder patients (CGI-BPD) was the primary outcome measure, and other scales and self-reports related to affect, behavior, psychosis, general psychopathology domains, and clinical safety were included. RESULTS: Analysis of variance indicated no statistically significant differences between ziprasidone and placebo in the CGI-BPD. Nor were significant differences observed between groups in depressive, anxiety, psychotic, or impulsive symptoms. The mean daily dose of ziprasidone was 84.1 mg/day (SD = 54.8; range, 40-200). The drug was seen to be safe, and no serious adverse effects were observed. CONCLUSION: This trial failed to show a significant effect of ziprasidone in patients with borderline personality disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00635921.

Clima familiar en pacientes con trastorno psicótico o afectivo / Family environment in patients with psychotic or affective disorder

El presente estudio intenta valorar el clima familiar en pacientes agudos hospitalizados, diagnosticados de trastorno psicótico o afectivo. Muestra: 31 pacientes y sus respectivas familias. Responden a la Family Environment Scale (FES) el paciente, y dos de los familiares que conviven con él. Los pacientes con trastorno afectivo puntúan más alto en las subescalas de "Cohesión" y "Expresividad"; mientras que los pacientes con trastorno psicótico tienen puntuaciones más elevadas en la subescala "Conflicto". En la subescala "Control", las familias de la muestra resultan ser menos "controladas" que las de la población general. Además, los pacientes psicóticos perciben a sus familias más "controladoras" que los pacientes afectivos (AU)

Trastorno esquizofreniforme. Estudio prospectivo de 5 años de seguimiento / Eschizophreniform disorder. A five year prospective study

Introducción: Estudio prospectivo de cinco años cuyo objetivo es evaluar la estabilidad temporal del diagnóstico de trastorno esquizofreniforme (TE) provisional en pacientes ingresados por un primer episodio psicótico. Se evalúan también las propiedades predictivas de las características de buen pronóstico. Material y métodos: La muestra consta de 38 pacientes (23 hombres y 15 mujeres) ingresados en el hospital entre 1996 y 1998. Se realizaron cuatro entrevistas de seguimiento: en el primer, segundo, tercer y quinto año. Los pacientes fueron evaluados mediante: la Brief Psychiatric Rating Scale (BPRS), la Escala de Evolución de Strauss-Carpenter, los diagnósticos en los ejes I-IV, la Escala de Evaluación de la Actividad Global (EEAG), el tratamiento en curso y variables demográficas. Resultados: 27 pacientes completaron el seguimiento de cinco años. El 25,9 por ciento mantenían el diagnóstico de TE a los cinco años y el 59,2 por ciento fueron clasificados dentro del espectro esquizofrénico. La presencia en el primer ingreso de un mínimo de dos características de buen pronóstico se asoció con una mejor evolución a los cinco años, pero no se asoció al mantenimiento del diagnóstico de TE. Después de cinco años de seguimiento, los pacientes que mantuvieron el diagnóstico de TE presentaron mejor evolución que los pacientes esquizofrénicos. Conclusiones: El diagnóstico TE provisional fue muy inestable a los cinco años de seguimiento. La mayoría de pacientes continuaron presentando síntomas y cumplieron criterios de esquizofrenia o trastorno esquizoafectivo. Los hallazgos sugieren una asociación entre las características de buen pronóstico y una mejor evolución, aunque no se observa asociación con el mantenimiento del diagnóstico TE (AU)