Testing the efficacy of INtegral Cognitive REMediation (INCREM) in major depressive disorder: study protocol for a randomized clinical trial.

BACKGROUND: Given the limitation of pharmacological treatments to treat cognitive symptoms in patients with Major Depressive Disorder (MDD), cognitive remediation programs has been proposed as a possible procognitive intervention but findings are not conclusive. This study investigates the efficacy of an INtegral Cognitive REMediation (INCREM) that includes a combination of a Functional Remediation (FR) strategy plus a Computerized Cognitive Training (CCT) in order to improve not only cognitive performance but also the psychosocial functioning and the quality of life. METHODS: A single blind randomized controlled clinical trial in 81 patients with a diagnosis of MDD in clinical remission or in partial remission. Participants will be randomized to one of three conditions: INCREM (FR + CCT), Psychoeducation plus online games and Treatment As Usual (TAU). Intervention will consist in 12 group sessions, of approximately 110 min once a week. The primary outcome measure will be % of change in psychosocial functioning after treatment measured by the Functional Assessment Short Test (FAST); additionally, number of sick leaves and daily activities will also be recorded as pragmatic outcomes. DISCUSSION: To our knowledge, this is the first randomized controlled clinical trial using a combination of two different approaches (FR + CCT) to treat the present cognitive deficits and to promote their improvements into a better psychosocial functioning. TRIAL REGISTRATION: Clinical Trials NCT03624621 . Date registered 10th of August 2018 and last updated 24th August 2018.

Lack of relationship between plasma levels of escitalopram and QTc-interval length.

Despite safety concerns raised by the European Medicines Agency (EMA), evidence supporting QT-lengthening effects of escitalopram is far to be conclusive. We aimed to evaluate the relationship between escitalopram plasma levels (Escit-PL) and corrected QT-interval length (QTc-length) in 91 outpatients recruited from a hospital setting. Fifteen patients had an abnormally prolonged QTc-interval, and 3 had QTc-intervals ≥500 ms. No correlation between Escit-PL and QTc-length was found (r = 0.08; p = 0.45). Linear/logistic regression analyses were also conducted taking into account potential confounders such as age, gender, personal history of heart disease, medication load and concomitant use of antipsychotic/tricyclic antidepressants. Escit-PL did not predict either QTc-length or abnormally prolonged QTc-interval. Only antipsychotics/tricyclics use (adjusted ß = 0.26, SE = 9.1; p = 0.01) was an independent predictor of QTc-length (R 2 = 0.096, F = 4.68, df = 2,88; p = 0.01). Only antipsychotics/tricyclics use (OR 3.56 [95% CI 1.01-12.52]; p < 0.05) and medication load (OR 1.32 [95% CI 1.06-1.64]; p < 0.01) were significantly associated with an increased risk of abnormally prolonged QTc-interval (Omnibus test χ 2 = 9.5, df = 2; p < 0.01). Our study did not find a significant relationship between Escit-PL and QTc-length even when recognized modulating factors of the QT-interval were controlled for. Concomitant use of other potentially arrhythmogenic agents may help to explain the apparent link between escitalopram and QT prolongation previously suggested. The advisability of maintaining the EMA warning is once again called into question.

Rationale and methods of the iFightDepression study: A double-blind, randomized controlled trial evaluating the efficacy of an internet-based self-management tool for moderate to mild depression.

BACKGROUND: During the last decade online interventions have emerged as a promising approach for patients with mild/moderate depressive symptoms, reaching at large populations and representing cost-effective alternatives. The main objective of this double-blind, randomized controlled trial is to examine the efficacy of an internet-based self-management tool (iFightDepression) for mild to moderate depression as an add-on to treatment as usual (TAU) versus internet-based psychoeducation plus TAU. METHODS: A total of 310 participants with major depression disorder (MDD) will be recruited at four different mental-health facilities in Spain. Participants will be randomly allocated to one of two study arms: iFightDepression (iFD) tool + TAU vs. internet-based psychoeducation + TAU. Both interventions last for 8 weeks and there is a 12 weeks follow up. The primary outcome measure is changes in depressive symptoms assessed with the Hamilton Depression Rating Scale. Additionally, pre-post interventions assessments will include socio-demographic data, a brief medical and clinical history and self-reported measures of depressive symptoms, quality of life, functional impairments and satisfaction with the iFD tool. DISCUSSION: iFightDepression is an easy-prescribed tool that could increase the efficacy of conventional treatment and potentially reach untreated patients, shortening waiting lists to receive psychological treatment. Confirming the efficacy of the iFD internet-based self-management tool as an add-on treatment for individuals with mild to moderate depression will be clinically-relevant. TRIAL REGISTRATION: Registration number NCT02312583 . Clinicaltrials.gov . December 4, 2014.

NATURALISTIC COURSE OF MAJOR DEPRESSIVE DISORDER PREDICTED BY CLINICAL AND STRUCTURAL NEUROIMAGING DATA: A 5-YEAR FOLLOW-UP.

BACKGROUND: Despite its high recurrence rate, major depression disorder (MDD) still lacks neurobiological markers to optimize treatment selection. The aim of this study was to examine the prognostic potential of clinical and structural magnetic resonance imaging (sMRI) in the long-term MDD clinical outcomes (COs). METHODS: Forty-nine MDD patients were grouped into one of four different CO categories according to their trajectory: recovery, partial remission, remission recurrence, and chronic depression. Regression models including baseline demographic, clinical, and sMRI data were used for predicting patients' COs and symptom severity 5 years later. RESULTS: The model including only clinical data explained 32.4% of the variance in COs and 55% in HDRS, whereas the model combining clinical and sMRI data increased up to 52/68%, respectively. A bigger volume of right anterior cingulate gyrus was the variable that best predicted COs. CONCLUSIONS: The findings suggest that the addition of sMRI brain data to clinical information in depressive patients can significantly improve the prediction of their COs. The dorsal part of the right anterior cingulate gyrus may act as a potential biomarker of long-term clinical trajectories.

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).

Neuropsychological effects of maintenance treatment with Clozapine in Treatment-Resistant Psychotic Disorder.

INTRODUCTION: Clozapine is a second-generation antipsychotic drug that is mainly prescribed for treatment-resistant psychotic disorder. It is known to have several undesirable side effects, including cognitive functional complaints, such as memory or attention. The aim of this work is to study if reduction of the dosage within the therapeutic margins could improve cognitive performance of Clozapine treated patients. To do so, a study was made of the relationship between Clozapine plasma levels and neuropsychological performance in patients undergoing Clozapine monotherapy. MATERIAL AND METHODS: This is a single-blind design study of the correlation between Clozapine plasma levels and neuropsychological testing in a sample of 19 patients with treatment-resistant psychotic disorder in whom Clozapine was the only psychotropic drug. Spearman correlations were carried out between neuropsychological variables and Clozapine plasma levels. Additionally, the sample was divided into two groups between patients with high Clozapine plasma drug levels (Clz pl≥300µg/L) and low ones (Clz pl<300 µg/L). MANOVA was performed to determine neuropsychological differences between the two groups. Subsequently, a linear regression model was carried out to predict neuropsychological performance. RESULTS: There was no significant Spearman correlation between neuropsychological scores and Clozapine plasma levels (p>0.1). MANOVA showed no significant differences between the two groups in any of the tests administered, although there was a trend towards significance in the number on attempts of the Card Sorting Test (WCST), where subjects with high levels of Clozapine showed worse performance (F=3.86; df=1.17; p=0.07). The linear regression model showed that only plasma levels significantly predicted executive performance, explaining 31% of the variance (F=3.62; df=2.16; p=0.05). CONCLUSION: No relationship between plasma levels of Clozapine and cognitive performance has been found. This result suggests that it is not desirable to reduce a relevant dose of Clozapine in patients with cognitive complaints.

Non-fatal suicide behaviours across phases in the COVID-19 pandemic: a population-based study in a Catalan cohort.

BACKGROUND: The COVID-19 pandemic has been extensively discussed in the context of its effect on mental health. Although global suicide rates have remained stable during the pandemic, the specific effect on non-fatal suicide behaviours during and after the pandemic remains underexplored. This study aims to investigate patterns of non-fatal suicide behaviours before, during, and after the pandemic. METHODS: In this cohort study, we used data from all hospitals in Catalonia, Spain, collected through the Catalan Suicide Risk Code, which is a specifically designed suicide attempt surveillance protocol, involving a face-to-face, in-depth psychiatric evaluation, after a Catalan resident presents any suicide risk behaviour in any public health-care setting. This evaluation centralises data from suicide registries across the territory. We included non-fatal suicide behaviours, meaning suicidal ideation or attempts that did not result in death, and excluded self-harm behaviours not judged to be linked with suicidal ideation. We considered three periods: the pre-confinement period (Jan 1, 2018, to the enforcement of the lockdown in Spain on March 14, 2020); the confinement period (March 14, 2020, to the end of lockdown on June 21, 2020); and the post-confinement period (June 21, 2020, to Dec 31, 2022). We used Bayesian structural time series models to assess the effect of pandemic phases on non-fatal suicide behaviours, and we ran stratified analyses by sex and age to identify distinct patterns among demographic cohorts. FINDINGS: We obtained 26 482 records from Jan 1, 2018, to Dec 31, 2022. The mean age was 37·94 years (SD 18·07), and the sample included 17 584 (66·4%) women and 8898 (33·6%) men. Data on ethnicity were not collected. Temporal trends showed a mild increase in non-fatal suicide behaviours from Jan 1, 2018, to March 13, 2020; a reduction during the confinement period; and a subsequent rise after confinement. Bayesian models suggested a significant causal effect of lockdown easing, resulting in a 50·77% increase in non-fatal suicide behaviours (95% credible interval [CrI] 26·62-76·58; p<0·0001). Stratified analyses indicated that the easing of lockdown resulted in a significant increase in non-fatal suicide behaviours among women (25·92%; 6·71-44·72; p=0·011) and among individuals aged 18 years and younger (72·75%; 38·81-108·11; p<0·0001). INTERPRETATION: This study provides a comprehensive examination of non-fatal suicide behaviours in Catalonia, Spain, emphasising the dynamics of different COVID-19 pandemic phases. The initial reduction during strict lockdown aligns with Joiner's Interpersonal Theory of Suicide, whereas the post-confinement rise reflects complex factors, including social isolation and economic challenges. Sex-specific and age-specific analyses underscore distinct vulnerabilities, emphasising the need for targeted preventive strategies. FUNDING: Centro de Investigación Biomédica en Red de Salud Mental annual budget of G21, Agència de Gestió d'Ajuts Universitaris i de Recerca of the Generalitat de Catalunya. TRANSLATIONS: For the Catalan and Spanish translations of the abstract see Supplementary Materials section.

Effects of illness duration and treatment resistance on grey matter abnormalities in major depression.

BACKGROUND: Findings of brain structural changes in major depressive disorder are still inconsistent, partly because some crucial clinical variables have not been taken into account. AIMS: To investigate the effect of major depressive disorder on grey matter volumes. METHOD: Voxel-based morphometry was used to compare 66 patients with depression at different illness stages (22 each with first-episode, remitted-recurrent and treatment resistant/chronic depression) with 32 healthy controls. Brain volumes were correlated with clinical variables. RESULTS: Voxel-based morphometry showed a significant group effect in right superior frontal gyrus, left medial frontal gyrus and left cingulate gyrus (P<0.05, family wise error-corrected). Patients whose condition was treatment resistant/chronic exhibited the smallest volumes in frontotemporal areas. Longer illness duration was negatively correlated with decreases in right medial frontal cortex and left insula. CONCLUSIONS: Frontotemporolimbic areas are smaller in the patients with severe depression and are associated with duration of illness, but not with medication patterns, suggesting negative effects of long-lasting major depressive disorder on grey matter.

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.

Response and Safety Outcomes in Treatment-Resistant Depression After Subcallosal Cingulate Gyrus Deep Brain Stimulation: Long-term Follow-up Study.

Objective: To replicate previous findings and to investigate related clinical factors of long-term benefits and safety of subcallosal cingulate gyrus deep brain stimulation (SCG-DBS) for treatment-resistant depression (TRD).Methods: Sixteen patients with TRD (with either major depressive disorder or bipolar disorder, DSM-IV and DSM-5 criteria) receiving chronic SCG-DBS were followed for up to 11 years (January 2008 to June 2019). Demographic, clinical, and functioning data were collected pre-surgery and during the follow-up. Response was defined as a ≥ 50% decrease from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D17) score, and remission was defined as ≤ 7 in the HAM-D17 score. The Illness Density Index (IDI) was used as a longitudinal measure of treatment effects. Survival analyses were performed for response outcomes and relapses.Results: Depressive symptoms were significantly decreased over time (F = 2.37; P = .04). Response and remission rates were 75% and 62.5% at individual endpoint. Based on Kaplan-Meier curve analysis, 55% of patients reached remission in 139 days. IDI curves showed sustained clinical improvements as measured with HAM-D17 and Clinical Global Impression and sustained functioning improvement as measured with Global Assessment of Functioning scores. The procedure was generally safe and well tolerated (122 adverse events across 81 patient-years, of which 25 were related to SCG-DBS). Two patients committed suicide long after surgery.Conclusions: SCG-DBS produced a robust and protracted improvement in most patients, which reinforces the possibility that SCG-DBS could be an alternative for patients with treatment-resistant unipolar or bipolar depression. Identification of clinical and neurobiological response predictors should guide the continuation of DBS for TRD, to obtain its indication soon.

If you feel you can't, you won't: the role of subjective and objective cognitive competence on psychosocial functioning in depression.

BACKGROUND: The purpose of this exploratory study is to examine the role of sociodemographic, clinical, and cognitive - both objective and subjective - factors in overall and in specific domains of psychosocial functioning, in patients with depression at different clinical states of the disease (remitted and non-remitted). METHODS: A sample of 325 patients with major depressive disorder, 117 in remission and 208 in non-remission, were assessed with a semi-structured interview collecting sociodemographic, clinical, cognitive (with neuropsychological tests and the Perceived Deficit Questionnaire), and functional (Functioning Assessment Short Test) characteristics. Backward regression models were conducted to determine associations of global and specific areas of functioning with independent factors, for both clinical states. RESULTS: Residual depressive symptomatology and self-appraisal of executive competence were significantly associated with psychosocial functioning in remitted patients, in overall and some subdomains of functioning, particularly cognitive and interpersonal areas. While depressive symptoms, executive deficits and self-appraisal of executive function were significantly related to functional outcomes in non-remitted patients, both in overall functioning and in most of subdomains. DISCUSSION: This study evidences the strong association of one's appraisal of executive competence with psychosocial functioning, together with depressive symptoms, both in remitted and non-remitted patients with depression. Therefore, to achieve full recovery, clinical management of patients should tackle not only the relief of core depressive symptoms, but also the cognitive ones, both those that are objectified with neuropsychological tests and those that are reported by the patients themselves.

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.

Randomized clinical trial of integral cognitive remediation program for major depression (INCREM).

BACKGROUND: Despite achieving clinical remission, patients with depression encounter difficulties to return to their premorbid psychosocial functioning. Cognitive dysfunction has been proposed to be a primary mediator of functional impairment. Therefore, the new non-pharmacological procognitive strategy INtegral Cognitive REMediation for Depression (INCREM) has been developed with the aim of targeting cognitive and psychosocial functioning. METHODS: This is a single-blind randomized controlled clinical trial with three treatment arms. Fifty-two depressed patients in clinical remission, with psychosocial difficulties and cognitive impairment, were randomly assigned to receive INCREM intervention, Psychoeducation programme, or treatment as usual. Patients were assessed before and after the study period, and six months after. The primary outcome was the change from baseline of patients' psychosocial functioning. Changes in cognitive functioning and other variables were considered secondary outcomes. RESULTS: The analysis showed a significant improvement in psychosocial functioning in the INCREM group, especially six months after the intervention, compared to patients who received the psychoeducation programme. An improvement in cognitive performance was also observed in the INCREM group. LIMITATIONS: This study includes a small sample size due to the anticipated end of the clinical trial because of the COVID-19 pandemic. DISCUSSION: These results provide preliminary evidence on the feasibility and potential efficacy of the INCREM program to improve not only cognitive performance but also psychosocial functioning in clinically remitted depressed patients, and such improvement is maintained six months after. It can be speculated that the maintenance is mediated by the cognitive enhancement achieved with INCREM.

Unhappy While Depressed: Examining the Dimensionality, Reliability and Validity of the Subjective Happiness Scale in a Spanish Sample of Patients with Depressive Disorders.

Despite the considerable amount of research evidence on the significant role of subjective happiness on mental health, there is no psychometric study of the Subjective Happiness Scale (SHS) in psychiatric samples. This study was aimed at exploring the psychometric properties of the SHS in a Spanish sample of patients with depressive disorders. Participants were 174 patients with a depressive disorder (70% diagnosed as major depressive disorder) who completed the SHS, the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), and the EQ-5D Visual Analogue Scale (EQ-5D VAS). Depressive symptoms were also assessed by means of the 17-item Hamilton Depression Rating Scale (HDRS17) and the Clinical Global Impression-Severity (CGI-S) Scale. Dimensionality, internal consistency reliability, construct validity, and responsiveness to change of the SHS were examined. Confirmatory factor analysis replicated the original one-factor structure of the scale. The SHS exhibited good-to-excellent results for internal consistency (α = 0.83) and for convergent [EQ-5D VAS (r = 0.71)] and divergent [QIDS-SR16 (r = -0.72), HDRS17 (r = -0.60) and CGI-S (r = -0.61)] construct validity. The ability of the SHS to differentiate between depression severity levels as well as its responsiveness to clinical change were both highly satisfactory (p < 0.001 in both cases). The SHS retained the soundness of psychometric properties showed in non-clinical samples in a sample of patients with depressive disorders, which supports its use as a reliable and valid outcome measure in the treatment of such disorders.

Glutamatergic and GABA-ergic abnormalities in First-episode depression. A 1-year follow-up 1H-MR spectroscopic study.

BACKGROUND: Previous magnetic resonance spectroscopic (MRS) studies have reported brain metabolic abnormalities in Major Depressive Disorder (MDD). Nevertheless, results have been inconsistent, focusing on fully developed major depression neglecting first episode patients (FED). Longitudinal studies have also been rare and with short follow-up periods. The aim of the current study was to investigate the differences between healthy controls and first episode patients at baseline, together with changes of metabolites after 1 year follow-up in the ventromedial prefrontal cortex. METHODS: 1H-MRS images were obtained from 64 healthy controls and 31 FED patients using a 3T Philips Achieva scanner and processed with TARQUIN software at baseline and after 1 year. Examined metabolites included Glx (corresponding to Glu+Gln-peak), Glu, NAAG, myo-Ins, Cr, GSH and GABA. Clinical improvement was assessed by HDRS-17 scale. Differences in the concentrations of metabolites were evaluated by MANOVA/MANCOVA and GLM repeated measures for longitudinal changes. RESULTS: FED patients had significantly decreased glutamate levels at baseline (p < 0.05) along with significantly elevated GABA (p < 0.01) compared to healthy controls. At the follow up, myo- Ins levels were significantly increased compared to baseline (p < 0.05) LIMITATIONS: The limited sample size, together with the unexpectedly high response rate after treatment (83%) might suggest decreased representativeness of the sample. CONCLUSIONS: Results indicate glutamatergic and GABAergic changes taking place within the ventromedial prefrontal region even at the early stage of depression prior to any medication treatment.

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

BACKGROUND: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. METHODS: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). FINDINGS: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). INTERPRETATION: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

Looking into the effect of multi-item symptom domains on psychometric characteristics of the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16).

Exploring depressive symptom severity is progressively shifting from the traditional assessment of symptom domains to detailed examination of individual symptoms. This study aimed at determining whether using an alternative scoring method (i.e., summing all scorable items instead of summing symptom domains) for the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) would not compromise the measurement properties. This is a secondary analysis of data collected in a psychometric study of the Spanish version of the QIDS-SR16. One hundred and sixty-six patients were assessed by means of the QIDS-SR16 and two interviewer-rated instruments: the Hamilton Depression Rating Scale and the Clinical Global Impression-Severity scale. Factor structure, internal consistency reliability and convergent construct validity of the QIDS-SR16 scored using the alternative method were examined. Exploratory factor analysis replicated the one-factor structure of the original scoring system. Good to excellent internal consistency and convergent validity were found, which did not differ significantly from the ones of the original scoring method. Using a simplified and easier scoring method, the Spanish QIDS-SR16 retained the soundness of psychometric characteristics of both the original English version and the Spanish one scored according to the original scoring system, supporting the alternative scoring method as a reliable and valid option.

Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study.

RATIONALE: To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT. OBJECTIVES: (123)I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc. MATERIALS AND METHODS: Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. (123)I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E (max) model. RESULTS: Mean SERTocc values were 66.4 +/- 9.5% in midbrain, 63.0 +/- 9.6% in thalamus, and 61.3 +/- 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 +/- 0.15; thalamus = 0.85 +/- 0.13; striatum = 0.70 +/- 0.07) and healthy volunteers (midbrain = 1.19 +/- 0.22; thalamus = 0.96 +/- 0.14; striatum = 0.67 +/- 0.15). The E (max) model returned a SERTocc(max) = 70.5% and a Cp(50) = 2.7 ng/ml. CONCLUSIONS: Using (123)I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E (max) model is suitable for the study of paroxetine Cp relationship to (123)I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic-pharmacodynamic relationships in drug development.

Double-blind, placebo-controlled study of dialectical behavior therapy plus olanzapine for borderline personality disorder.

OBJECTIVE: The aim of this study was to determine the efficacy and safety of dialectical behavior therapy plus olanzapine compared with dialectical behavior therapy plus placebo in patients with borderline personality disorder. METHOD: Sixty patients with borderline personality disorder were included in a 12-week, double-blind, placebo-controlled study. All patients received dialectical behavior therapy and were randomly assigned to receive either olanzapine or placebo following a 1-month baseline period. RESULTS: Seventy percent of the patients completed the 4-month trial. Combined treatment showed an overall improvement in most symptoms studied in both groups. Olanzapine was associated with a statistically significant improvement over placebo in depression, anxiety, and impulsivity/aggressive behavior. The mean dose of olanzapine was 8.83 mg/day. CONCLUSIONS: A combined psychotherapeutic plus pharmacological approach appears to lower dropout rates and constitutes an effective treatment for borderline personality disorder.