Increased grey matter volumes in the temporal lobe and its relationship with cognitive functioning in euthymic patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodic mood dysregulation, although a significant portion of patients suffer persistent cognitive impairment during euthymia. Previous magnetic resonance imaging (MRI) research suggests BD patients may have accelerated brain aging, observed as lower grey matter volumes. How these neurostructural alterations are related to the cognitive profile of BD is unclear. METHODS: We aim to explore this relationship in euthymic BD patients with multimodal structural neuroimaging. A sample of 27 euthymic BD patients and 24 healthy controls (HC) underwent structural grey matter MRI and diffusion-weighted imaging (DWI). BD patient's cognition was also assessed. FreeSurfer algorithms were used to obtain estimations of regional grey matter volumes. White matter pathways were reconstructed using TRACULA, and four diffusion metrics were extracted. ANCOVA models were performed to compare BD patients and HC values of regional grey matter volume and diffusion metrics. Global brain measures were also compared. Bivariate Pearson correlations were explored between significant brain results and five cognitive domains. RESULTS: Euthymic BD patients showed higher ventricular volume (F(1, 46) = 6.04; p = 0.018) and regional grey matter volumes in the left fusiform (F(1, 46) = 15.03; pFDR = 0.015) and bilateral parahippocampal gyri compared to HC (L: F(1, 46) = 12.79, pFDR = 0.025/ R: F(1, 46) = 15.25, pFDR = 0.015). Higher grey matter volumes were correlated with greater executive function (r = 0.53, p = 0.008). LIMITATIONS: We evaluated a modest sample size with concurrent pharmacological treatment. CONCLUSIONS: Higher medial temporal volumes in euthymic BD patients may be a potential signature of brain resilience and cognitive adaptation to a putative illness neuroprogression. This knowledge should be integrated into further efforts to implement imaging into BD clinical management.

Blunted neurobiological reactivity and attentional bias to threat underlie stress-related disorders in women survivors of intimate partner violence.

BACKGROUND: Intimate partner violence (IPV) alters women's neurobiological stress response systems. We propose that individual differences early in the attentional processing of threats are associated with these neurobiological mechanisms and contribute to mental illness in this population. METHODS: We assessed attentional bias in relation to threat (AB) in women survivors of IPV (n = 69) and controls (n = 36), and examined overall cortisol secretion using hair cortisol (HC), and stress responsiveness measuring salivary cortisol and α-amylase (sAA) before (T0), and after (T1, T2) an acute psychosocial stress task (Trier Social Stress Test). We used repeated-measures ANCOVAs to explore the associations between Group (IPV, control) and AB with acute stress response, and regression models to examine the associations with mental health symptoms. RESULTS: There were no between-group differences in HC levels. An interaction between Group and AB was found regarding cortisol reactivity (p < 0.05). IPV women with threat avoidance AB showed a blunted cortisol response compared to controls and to IPV participants with threat vigilance AB. The association between sAA reactivity and the interaction between Group, AB, and time approached significance (p = 0.07), with a trend to lower sAA levels particularly in IPV women with threat avoidance AB. Group and cortisol reactivity were associated with symptoms of depression, generalized anxiety, and post-traumatic stress disorder (8-20% explained variance). CONCLUSIONS: Threat avoidance AB is associated with blunted acute cortisol response among women exposed to chronic stress (IPV). Experiencing IPV and acute cortisol response appear to be clearly implicated in long-term mental health problems.

Disrupted network switching in euthymic bipolar disorder: Working memory and self-referential paradigms.

BACKGROUND: Patients with bipolar disorder (BD) frequently suffer from neurocognitive deficits that can persist during periods of clinical stability. Specifically, impairments in executive functioning such as working memory and in self-processing have been identified as the main components of the neurocognitive profile observed in euthymic BD patients. The study of the neurobiological correlates of these state-independent alterations may be a prerequisite to develop reliable biomarkers in BD. METHODS: A sample of 27 euthymic BD patients and 25 healthy participants (HC) completed working memory and self-referential functional Magnetic Resonance Imaging (fMRI) tasks. Activation maps obtained for each group and contrast images (i.e., 2-back > 1-back/self > control) were used for comparisons between patients and HC. RESULTS: Euthymic BD patients, in comparison to HC, showed a higher ventromedial prefrontal cortex activation during working memory, a result driven by the lack of deactivation in BD patients. In addition, euthymic BD patients displayed a greater dorsomedial and dorsolateral prefrontal cortex activation during self-reference processing. LIMITATIONS: Pharmacotherapy was described but not included as a confounder in our models. Sample size was modest. CONCLUSION: Our findings revealed a lack of deactivation in the anterior default mode network (aDMN) during a working memory task, a finding consistent with prior research in BD patients, but also a higher activation in frontal regions within the central executive network (CEN) during self-processing. These results suggest that an imbalance of neural network dynamics underlying external/internal oriented cognition (the CEN and the aDMN, respectively) may be one of the first reliable biomarkers in euthymic bipolar patients.

Suicide-related thoughts and behavior and suicide death trends during the COVID-19 in the general population of Catalonia, Spain.

The COVID-19 pandemic is expected to increase suicidal behavior. However, data available to date are inconsistent. This study examines suicidal thoughts and behaviors and suicide trends in 2020 relative to 2019 as an approximation to the impact of the pandemic on suicidal behavior and death in the general population of Catalonia, Spain. Data on suicide-related thoughts and behaviors (STBs) and suicidal mortality were obtained from the Catalonia Suicide Risk Code (CSRC) register and the regional police, respectively. We compared the monthly crude incidence of STBs and suicide mortality rates of 2020 with those of 2019. Joinpoint regression analysis was used to assess changes in trends over time during the studied period. In 2020, 4,263 consultations for STBs and 555 suicide deaths were registered in Catalonia (approx. 7.5 million inhabitants). Compared to 2019, in 2020 STBs rates decreased an average of 6.3% (incidence rate ratio, IRR=0.94, 95% CI 0,90-0,98) and overall suicide death rates increased 1.2% (IRR=1.01, 95% CI 0.90-1.13). Joinpoint regression results showed a substantial decrease in STBs rates with a monthly percent change (MPC) of -22.1 (95% CI: -41.1, 2.9) from January-April 2020, followed by a similar increase from April-July 2020 (MPC=24.7, 95% CI: -5.9, 65.2). The most restrictive measures implemented in response to the COVID-19 pandemic reduced consultations for STBs, suggesting that the "stay at home" message may have discouraged people from contacting mental health services. STBs and mortality should continue to be monitored in 2021 and beyond to understand better the mid-to-long term impact of COVID-19 on suicide trends.

Therapeutic drug monitoring is useful when pharmacogenetic assessment is unavailable: case report of delusional disorder / La monitorización terapéutica de fármacos es útil cuando la evaluación farmacogenética no está disponible: caso clínico de trastorno delirante

Antipsychotic plasma levels have been extensively used in the assessment of poor treatment response, lack of adherence and adverse events in delusional disorder. It has not been used as an indicator of metabolizer status, to determine whether a delusional disorder patient is a poor, intermediate, or ultra-rapid metabolizer of antipsychotics. Pharmacogenetic probes are, of course, the right method for the latter task, but they are not readily available for clinical use. We report the case of a 46-year-old woman with delusional disorder who developed unexpected adverse effects to treatment with relatively low dose risperidone and poor symptomatic response. Blood level monitoring indicated high levels of risperidone and a high concentration-to-dose ratio, which suggested accumulation of unmetabolized risperidone. Paradoxically, extrapyramidal side effects increased when, after reducing the risperidone dose, 5 mg/day of aripiprazole was added. Consequently, the patient was switched to olanzapine 5 mg/day. Sertraline 150 mg/day was later added for comorbid depression. A complete symptomatic response was achieved. Although other factors may well have been at play, this sequence of events suggests that the patient was a slow metabolizer of CYP2D6, which metabolizes both risperidone and aripiprazole. With pharmacogenetic assessment not available, therapeutic drug monitoring helped clinicians decide on appropriate management

Los niveles plasmáticos de antipsicóticos han sido extensamente utilizados para la evaluación de la pobre respuesta terapéutica, la falta de adherencia y los eventos adversos en pacientes con trastorno delirante. No han sido frecuentemente utilizados como indicadores del estado metabólico, para determinar si un paciente con trastorno delirante es metabolizador pobre, intermedio o metabolizador ultra-rápido de antipsicóticos. Los test de farmacogenética son, por supuesto, el método más idóneo para la última tarea, pero no son fáciles de obtener para su uso clínico. Reportamos el caso de una mujer de 46 años de edad con trastorno delirante que ha desarrollado efectos adversos inesperados con el tratamiento a dosis bajas de risperidona, y una pobre respuesta clínica. La monitorización de niveles plasmáticos indicó niveles elevados de risperidona y una ratio elevada concentración-dosis, que sugirió acumulación de risperidona no adecuadamente metabolizada. Paradójicamente, los efectos secundarios se incrementaron, cuando al reducir la dosis de risperidona, se añadió aripiprazol 5mg/día. Por ello, se realizó un cambio a olanzapina 5 mg/día. Se añadió sertralina 150 mg/día posteriormente para el tratamiento de síntomas depresivos comórbidos. Se alcanzó una respuesta clínica completa. A pesar de que otros factores pudieran haber contribuido a ello, la secuencia de eventos sugiere que la paciente pudiera ser metabolizadora lenta del CYP2D6, que metaboliza risperidona y aripiprazol. En caso de no disponibilidad de tests farmacogenéticos, la monitorización de niveles plasmáticos, ayudó a los clínicos a decidir el manejo apropiado del paciente

Efficacy and safety of oncoplastic surgery plus drug therapy for chronic tuberculous granulomatous mastitis.

BACKGROUND: Chronic tuberculous granulomatous mastitis (CTGM) is a rare form of tuberculosis (TB) treated primarily with anti-TB drugs. Oncoplastic surgery (OS) has been proposed as adjuvant therapy for CTGM.METHOD: We followed for 1 year every CTGM patients and assessed the efficacy (defined as non-recurrence and no need for corticosteroids) and safety attributable to the standard anti-TB drugs therapy with and without OS.RESULTS: We analysed 128 CTGM cases, including 78 (61%) treated with OS plus anti-TB drugs and 50 (39%) with anti-TB drugs only. We observed a significantly higher efficacy among those exposed vs. unexposed to OS (100% vs. 92%; prevalence ratio [PR] 1.09, 95% CI 1.00-1.18), with no difference in the number of complications (21% vs. 8%; PR 2.56, 95% CI 0.91-7.26). We also observed that the incidence of post-operative complications decreased by 50% when OS was postponed from after Month 1 to after completing Month 2 of anti-TB drugs treatment (19% to 8%; PR 0.46, 95% CI 0.13-1.62).CONCLUSION: OS appears to represent an efficacious and safe adjuvant therapy when combined with anti-TB drugs in the treatment of CTGM patients, but clinical trials are needed to prove this observation.

Prefrontal-amygdala connectivity in trait anxiety and generalized anxiety disorder: Testing the boundaries between healthy and pathological worries.

BACKGROUND: Current brain-based theoretical models of generalized anxiety disorder (GAD) suggest a dysfunction of amygdala-ventromedial prefrontal cortex emotional regulatory mechanisms. These alterations might be reflected by an altered resting state functional connectivity between both areas and could extend to vulnerable non-clinical samples such as high worriers without a GAD diagnosis. However, there is a lack of information in this regard. METHODS: We investigated differences in resting state functional connectivity between the basolateral amygdala and the ventromedial prefrontal cortex (amygdala-vmPFC) in 28 unmedicated participants with GAD, 28 high-worriers and 28 low-worriers. We additionally explored selected clinical variables as predictors of amygdala-vmPFC connectivity, including anxiety sensitivity. RESULTS: GAD participants presented higher left amygdala-vmPFC connectivity compared to both groups of non-GAD participants, and there were no differences between the latter two groups. In our exploratory analyses, concerns about the cognitive consequences of anxiety (the cognitive dimension of anxiety sensitivity) were found to be a significant predictor of the left amygdala-vmPFC connectivity. LIMITATIONS: The cross-sectional nature of our study preclude us from assessing if functional connectivity measures and anxiety sensitivity scores entail an increased risk of GAD. CONCLUSIONS: These results suggest a neurobiological qualitative distinction at the level of the amygdala-vmPFC emotional-regulatory system in GAD compared to non-GAD participants, either high- or low-worriers. At this neural level, they question previous hypotheses of continuity between high worries and GAD development. Instead, other anxiety traits such as anxiety sensitivity might confer a greater proneness to the amygdala-vmPFC connectivity alterations observed in GAD.

Clinical and microbiological evaluation of the effect of Lactobacillus reuteri in the treatment of mucositis and peri-implantitis: A triple-blind randomized clinical trial.

BACKGROUND AND OBJECTIVE: Oral probiotics appear to improve the treatment of periodontal diseases but there is limited evidence on their efficacy in the treatment of peri-implant diseases. The objective of the present study was to evaluate, clinically and microbiologically, the effect of the oral probiotic, Lactobacillus reuteri Prodentis, as adjuvant to non-surgical mechanical therapy in implants with mucositis or peri-implantitis, placed in patients with a history of periodontal disease. MATERIAL AND METHODS: A randomized, controlled, parallel-design, triple-blind prospective clinical study was designed. Patients included in the study were partially edentulous and had implants with mucositis or peri-implantitis. Implants with radiographic bone loss of ≥5 mm and/or ≥50% of the implant length were excluded, and only one implant per patient was included. After non-surgical mechanical therapy, subjects were randomly assigned to take either 1 probiotic lozenge or 1 placebo lozenge every day for 30 days. Clinical measurements were taken in the whole mouth (general plaque index and general bleeding on probing) and at the implant site (probing pocket depth, plaque index and bleeding on probing) at baseline and 30 and 90 days Microbiological examination (to identify Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia, Peptostreptococcus micros, Fusobacterium nucleatum, Campylobacter rectus and Eikenella corrodens) was performed at the same study time points that clinical measurements were made. RESULTS: A total of 44 patients - 22 with mucositis and 22 with peri-implantitis - randomly received treatment with either probiotic or placebo. The probiotic L. reuteri, together with mechanical therapy, produced an additional improvement over treatment with mechanical therapy alone, both in the general clinical parameters of patients with mucositis (bleeding on probing) and at the level of implants with mucositis (probing pocket depth) or peri-implantitis (bleeding on probing and probing pocket depth). However, L. reuteri had a very limited effect on the peri-implant microbiota because the only parameter in which a significant decrease was found was the bacterial load of P. gingivalis in implants with mucositis (P = .031). CONCLUSION: The administration of a daily lozenge of L. reuteri for 30 days, together with mechanical debridement of the whole mouth, improved the clinical parameters of implants with mucositis or peri-implantitis over a period of at least 90 days, but the microbiological effect was much more limited. Probiotics provide an alternative therapeutic approach to consider in the prevention and treatment of peri-implant diseases, but further long-term prospective studies with standardized variables are needed.

Adaptation and validation of the Spanish version of the Mood Disorder Questionnaire for the detection of bipolar disorder.

OBJECTIVE: The Mood Disorder Questionnaire (MDQ) is an instrument for the detection of patients with bipolar disorder (BD). The original English version is validated in both the psychiatric and the general population, but a validated Spanish version is not yet available. Psychometric properties of the Spanish adaptation of the MDQ in psychiatry are described. METHODS: The MDQ is a self-administered questionnaire comprising a list of 13 hypomanic symptoms and two questions about concurrence of symptoms and functional impairment caused by the symptoms. We selected patients from 15 psychiatric outpatient departments, diagnosed with BD type I and II (BDI and BDII) and major depression (MD) according to DSM-IV-TR criteria (concurrent validity instrument). A control group of healthy subjects (HS) was selected. The patient-selection criteria included stability of the disorder and pharmacological treatment. The MDQ was administered to 236 subjects, distributed among the four groups, on two occasions, four weeks apart. We analysed the internal consistency, test-retest reliability, and discriminative capacity of the MDQ for the detection of patients with BD. RESULTS: Concurrent validity based on diagnosis according to DSM-IV-TR was 0.83. The internal consistency, evaluated by Cronbach's alpha, was 0.90. The mean (SD) number of affirmative responses by group was: 9.8 (2.4) for BDI, 8.5 (2.8) for BDII, 2.7 (2.2) for MD, and 1.02 (1.9) for HS. Statistically significant differences between all the groups were found (Kruskal-Wallis test, p < 0.001). Concurrent validity using the diagnostic variable was 0.83. Test-retest reliability was 0.92. We analysed the scale's discriminative capacity, revealing a sensitivity value of 0.60 [95% confidence interval (CI) = 0.51-0.69] and a specificity value of 0.98 (95% CI = 0.94-0.99) in the detection of BD. The positive and negative probability ratios were 35.5 and 2.4, respectively. If we consider only seven positive responses as the discriminative criterion, sensitivity increases to 0.81 (95% CI = 0.73-0.88), the specificity value is 0.95 (95% CI = 0.89-0.98) and the positive and negative probability quotients are 16 and 5.3. CONCLUSIONS: The psychometric characteristics of the Spanish version are similar to those of the original version. In the Spanish adaptation of the MDQ, seven positive responses to hypomanic symptoms show a good discriminative capacity for BD in patients attending psychiatric outpatient facilities; therefore, this cut-off score is proposed for the detection of BD in psychiatric outpatients.

The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia.

A 24-week, double-blind, randomized trial was performed to compare the efficacy and tolerability of venlafaxine and paroxetine in patients with major depression or dysthymia. Outpatients aged 18-70 years with a baseline score of 17 on the 21-item Hamilton Depression Rating Scale (HAM-D) were eligible. Patients were randomly assigned to venlafaxine, 37.5 mg, in the morning and evening or paroxetine, 20 mg, in the morning and placebo in the evening, which could be increased to venlafaxine, 75 mg twice daily, or paroxetine, 20 mg twice daily, after 4 weeks. Efficacy was assessed with the 21-item HAM-D, the Montgomery-Asberg Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impressions Scale. Forty-one patients were randomized to venlafaxine and 43 to paroxetine. At week 6, a response was observed in 55% of patients on venlafaxine and 29% on paroxetine (P = 0.03). At week 12, significantly (P = 0.011) more patients in the venlafaxine group had a HAM-D remission score of 8 or less (59% versus 31%). Discontinuation for any reason occurred in 16 (39%) patients on venlafaxine and 11 (26%) on paroxetine. The most common adverse events were nausea (28%), headache (18%) and dry mouth (15%) with venlafaxine and headache (40%) and constipation (16%) with paroxetine. Venlafaxine was effective and well tolerated for the treatment of patients with mild to moderate depression or dysthymia. A consistently higher proportion of patients had a response or remission on venlafaxine than on paroxetine.

Haloperidol: therapeutic window in schizophrenia.

Twenty-two schizophrenic inpatients were treated for 3 weeks with three randomly fixed oral doses of haloperidol (10, 20, or 30 mg). Analysis of the results by a nonlinear regression model revealed a curvilinear relationship between haloperidol levels in plasma and clinical response, as assessed on the Brief Psychiatric Rating Scale (pseudo-R2 = 0.85, F = 17.7, p < 0.001, correlation between coefficients ranged from 0.99 to -0.52). This curve defines roughly three drug level ranges (low, < 5.5 ng/ml; optimal, 5.5 to 14.4 ng/ml; and high or toxic, > 14.4 ng/ml), which are significant for clinical practice. Patients with high levels improve to a lesser extent or even worsen in negative symptoms, showing a nonstatistically significant trend to present more extrapyramidal symptoms. Our data thus support the existence of a therapeutic window for haloperidol. Schizophrenic patients with acute exacerbation and drug levels in this range would have a greater probability of global clinical improvement.

Positive versus negative symptoms in schizophrenia: response to haloperidol.

1. Clinical response to treatment with haloperidol was studied in 20 schizophrenic inpatients with acute exacerbation (DSM-IIIR). 2. Patients were assigned to fixed doses of haloperidol (10, 20 or 30 mg/day) for three weeks. Clinical assessment was made using scales SAPS, SANS, BPRS and Simpson-Angus Scale for rating of extrapyramidal side effects. 3. Sixteen patients showed forty per cent or more decrease in positive symptoms assessed by SAPS, being considered the group of responders. Six out of the twenty patients showed improvement in negative symptoms assessed by SANS (improvement above 30%). 4. Clinical predictors of response were only identified for SAPS. The group of responders showed higher basal scores in total scale and formal thought disorder. 5. Negative symptoms responsive to treatment were affective flattening and alogia. Improvement in negative symptoms was independent from that in positive ones. 6. Socio-demographic predictors of clinical response were not found. No differences in clinical response were found in relation to the dose administered. 7. The results of our study suggest that negative symptomatology improves in a scheduled treatment with haloperidol. Assessment of negative symptoms may be useful in the evaluation of treatment of acute schizophrenia.