Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.

BACKGROUND AND OBJECTIVE: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine. METHODS: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model. RESULTS: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited. CONCLUSIONS: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression.

BACKGROUND: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. METHODS: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient's response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). RESULTS: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. CONCLUSIONS: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression.

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.

Subcutaneous Ketamine in Depression: A Systematic Review.

Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.

INTRODUCTION AND OBJECTIVES: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

Transcranial direct current stimulation (tDCS) in elderly with mild cognitive impairment: A pilot study.

Transcranial direct current stimulation (tDCS) is a non-invasive, painless and easy-to use-technology. It can be used in depression, schizophrenia and other neurological disorders. There are no studies about longer usage protocols regarding the ideal duration and weekly frequency of tDCS. OBJECTIVE: to study the use of tDCS twice a week for longer periods to improve memory in elderly with MCI. METHODS: a randomized double-blind controlled trial of anodal tDCS on cognition of 58 elderly aged over 60 years was conducted. A current of 2.0 mA was applied for 30 minutes for 10 sessions, twice a week. The anode was placed over the left dorsolateral prefrontal cortex (LDLFC). Subjects were evaluated before and after 10 sessions by the following tests: CAMCOG, Mini-Mental State Examination (MMSE), Trail Making, Semantic Verbal Fluency (Animals), Boston naming, Clock Drawing Test, Word list memory (WLMT), Direct and Indirect Digit Order (WAIS-III and WMS-III) and N-back. RESULTS: After 10 sessions of tDCS, significant group-time interactions were found for the CAMCOG - executive functioning (χ2 = 3.961, p = 0.047), CAMCOG - verbal fluency (χ2 = 3.869, p = 0.049), CAMCOG - Memory recall (χ2 = 9.749, p = 0.004), and WMLT - recall (χ2 = 7.254, p = 0.007). A decline in performance on the CAMCOG - constructional praxis (χ2 = 4.371, p = 0.037) was found in the tDCS group after intervention. No significant differences were observed between the tDCS and Sham groups for any other tasks. CONCLUSION: tDCS at 2 mA for 30 min twice a week over 5 consecutive weeks proved superior to placebo (Sham) for improving memory recall, verbal fluency and executive functioning in elderly with MCI.

A ETCC (estimulação transcraniana por corrente contínua) é uma tecnologia não-invasiva, indolor e de fácil utilização. Pode ser usada na depressão, esquizofrenia e outros distúrbios neurológicos. Não há orientações ideais sobre o uso de protocolos mais longos quanto à duração e frequência semanal da ETCC. OBJETIVO: estudar o uso de ETCC duas vezes por semana por 5 semanas em idosos com CCL. MÉTODOS: o estudo foi controlado, randomizado, duplo-cego com ETCC anódica em 58 idosos acima de 60 anos. Uma corrente de 2,0 mA foi aplicada por 30 minutos durante 10 sessões consecutivas, 2 vezes por semana. O ânodo foi colocado no córtex pré-frontal dorsolateral esquerdo (LDLFC). Os pacientes foram avaliados antes e após 10 sessões pelos testes: CAMCOG, Mini-Exame do Estado Mental (MMSE), Trilhas, Fluência Verbal Semântica - Animais, Boston, Relógio, Memória da Lista de Palavras (WLMT), Dígitos - ordem direta e indireta (WAIS-III e WMS-III) e N-back. RESULTADOS: foram encontradas interações significativas (tempo/grupo) para CAMCOG - funcionamento executivo (χ2 = 3,961, p = 0,047), CAMCOG - fluência verbal (χ2 = 3,869, p = 0,049), CAMCOG - recuperação da memória (χ2 = 9.749, p = 0,004), WMLT - recordação (χ2 = 7,254, p = 0,007). Foi observado um declínio no grupo ETCC após a intervenção para CAMCOG - praxia construtiva (χ2 = 4,371, p = 0,037). Não encontramos diferenças significativas entre os grupos ETCC e placebo para outros testes. CONCLUSÃO: A ETCC de 2 mA por 30 min, 2x por semana, por 5 semanas consecutivas, é superior ao placebo (Sham) na melhoria da recuperação de memória, fluência verbal e funcionamento executivo em idosos com CCL.

Transcranial direct current stimulation (tDCS) in elderly with mild cognitive impairment: A pilot study / Estimulação Transcraniana por Corrente Direta (ETCD) em idosos com comprometimento cognitivo leve: um estudo piloto

ABSTRACT. Transcranial direct current stimulation (tDCS) is a non-invasive, painless and easy-to use-technology. It can be used in depression, schizophrenia and other neurological disorders. There are no studies about longer usage protocols regarding the ideal duration and weekly frequency of tDCS. Objective: to study the use of tDCS twice a week for longer periods to improve memory in elderly with MCI. Methods: a randomized double-blind controlled trial of anodal tDCS on cognition of 58 elderly aged over 60 years was conducted. A current of 2.0 mA was applied for 30 minutes for 10 sessions, twice a week. The anode was placed over the left dorsolateral prefrontal cortex (LDLFC). Subjects were evaluated before and after 10 sessions by the following tests: CAMCOG, Mini-Mental State Examination (MMSE), Trail Making, Semantic Verbal Fluency (Animals), Boston naming, Clock Drawing Test, Word list memory (WLMT), Direct and Indirect Digit Order (WAIS-III and WMS-III) and N-back. Results: After 10 sessions of tDCS, significant group-time interactions were found for the CAMCOG - executive functioning (χ2 = 3.961, p = 0.047), CAMCOG - verbal fluency (χ2 = 3.869, p = 0.049), CAMCOG - Memory recall (χ2 = 9.749, p = 0.004), and WMLT - recall (χ2 = 7.254, p = 0.007). A decline in performance on the CAMCOG - constructional praxis (χ2 = 4.371, p = 0.037) was found in the tDCS group after intervention. No significant differences were observed between the tDCS and Sham groups for any other tasks. Conclusion: tDCS at 2 mA for 30 min twice a week over 5 consecutive weeks proved superior to placebo (Sham) for improving memory recall, verbal fluency and executive functioning in elderly with MCI.

RESUMO. A ETCC (estimulação transcraniana por corrente contínua) é uma tecnologia não-invasiva, indolor e de fácil utilização. Pode ser usada na depressão, esquizofrenia e outros distúrbios neurológicos. Não há orientações ideais sobre o uso de protocolos mais longos quanto à duração e frequência semanal da ETCC. Objetivo: estudar o uso de ETCC duas vezes por semana por 5 semanas em idosos com CCL. Métodos: o estudo foi controlado, randomizado, duplo-cego com ETCC anódica em 58 idosos acima de 60 anos. Uma corrente de 2,0 mA foi aplicada por 30 minutos durante 10 sessões consecutivas, 2 vezes por semana. O ânodo foi colocado no córtex pré-frontal dorsolateral esquerdo (LDLFC). Os pacientes foram avaliados antes e após 10 sessões pelos testes: CAMCOG, Mini-Exame do Estado Mental (MMSE), Trilhas, Fluência Verbal Semântica - Animais, Boston, Relógio, Memória da Lista de Palavras (WLMT), Dígitos - ordem direta e indireta (WAIS-III e WMS-III) e N-back. Resultados: foram encontradas interações significativas (tempo/grupo) para CAMCOG - funcionamento executivo (χ2 = 3,961, p = 0,047), CAMCOG - fluência verbal (χ2 = 3,869, p = 0,049), CAMCOG - recuperação da memória (χ2 = 9.749, p = 0,004), WMLT - recordação (χ2 = 7,254, p = 0,007). Foi observado um declínio no grupo ETCC após a intervenção para CAMCOG - praxia construtiva (χ2 = 4,371, p = 0,037). Não encontramos diferenças significativas entre os grupos ETCC e placebo para outros testes. Conclusão: A ETCC de 2 mA por 30 min, 2x por semana, por 5 semanas consecutivas, é superior ao placebo (Sham) na melhoria da recuperação de memória, fluência verbal e funcionamento executivo em idosos com CCL.

Efficacy of topiramate in the treatment of crack cocaine dependence: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: We performed a double-blind, randomized, placebo-controlled trial to assess the efficacy of topiramate in the treatment of crack cocaine dependence. METHOD: Sixty men who were dependent on cocaine (DSM-IV) (exclusive use of crack cocaine) were selected. The subjects were randomly assigned to either a topiramate group (subjects received 50-200 mg of topiramate per day for 12 weeks) or a control group (subjects received placebo). The initial daily treatment dose was 50 mg, and this dose was increased weekly at increments of 25 to 50 mg, based on the subject's tolerability, to a maximum of 200 mg. All of the subjects also participated in motivational interviews and group therapy. The primary outcome measures were detection of benzoylecgonine in the urine, study retention, frequency of cocaine smoking, amount of cocaine use, and mean amount of money spent on cocaine per week. The study was conducted from February 2013 to February 2014. RESULTS: Twenty-nine subjects in the topiramate group and 29 subjects in the control group completed the study. Longitudinal assessment revealed that retention was not significant (odds ratio [OR] = 1.072, P = .908) between the 2 groups. Negative results from a urine test for benzoylecgonine (a cocaine metabolite), which is a measure of cocaine abstinence, were more frequently obtained from the topiramate group (OR = 8.687, P < .001). Topiramate reduced the quantity of cocaine used (mean reduction = -3.108 g, P < .001), the frequency of cocaine use (mean = -0.784 times per week, P = .005), and the amount of money spent on cocaine (mean [US dollars] = -$25.38, P = .015; this variable did not achieve statistical significance after Bonferroni correction) compared with the placebo during the 12 weeks (or 84 days) of the assessment. However, the differences in reductions between the 2 groups in the quantity of cocaine used, the frequency of cocaine use, and money spent on cocaine over time (time × group interaction) were present only during the first 4 weeks, and none of these variables by 12 weeks. The studied groups did not differ with regard to secondary end points, such as study dropout and the number of subjects who reported side effects. CONCLUSIONS: The present findings indicate that topiramate is effective and safe and thus reinforce previous data suggesting that topiramate is a potentially useful treatment for crack cocaine dependence. However, we found that topiramate is only useful as an adjunctive treatment during the first 4 weeks of the treatment. Future studies with larger samples are needed to confirm these results. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-3vwfjs and UTN: U1111-1131-4443.

Default mode network maturation and psychopathology in children and adolescents.

BACKGROUND: The human default mode (DMN) is involved in a wide array of mental disorders. Current knowledge suggests that mental health disorders may reflect deviant trajectories of brain maturation. METHOD: We studied 654 children using functional magnetic resonance imaging (fMRI) scans under a resting-state protocol. A machine-learning method was used to obtain age predictions of children based on the average coefficient of fractional amplitude of low frequency fluctuations (fALFFs) of the DMN, a measure of spontaneous local activity. The chronological ages of the children and fALFF measures from regions of this network, the response and predictor variables were considered respectively in a Gaussian Process Regression. Subsequently, we computed a network maturation status index for each subject (actual age minus predicted). We then evaluated the association between this maturation index and psychopathology scores on the Child Behavior Checklist (CBCL). RESULTS: Our hypothesis was that the maturation status of the DMN would be negatively associated with psychopathology. Consistent with previous studies, fALFF significantly predicted the age of participants (p < .001). Furthermore, as expected, we found an association between the DMN maturation status (precocious vs. delayed) and general psychopathology scores (p = .011). CONCLUSIONS: Our findings suggest that child psychopathology seems to be associated with delayed maturation of the DMN. This delay in the neurodevelopmental trajectory may offer interesting insights into the pathophysiology of mental health disorders.

Cannabidiol and Sodium Nitroprusside: Two Novel Neuromodulatory Pharmacological Interventions to Treat and Prevent Psychosis.

Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.

Reduction of anterior cingulate in adults with urban violence-related PTSD.

BACKGROUND: To evaluate differences in limbic structure volume of subjects exposed to urban violence during adulthood, between those who developed posttraumatic stress disorder (with PTSD) and resilient matched controls (without PTSD). METHODS: Limbic volumetric measures of 32 subjects with PTSD and 32 subjects without PTSD who underwent brain MRI were analyzed in an epidemiological study in the city of Sao Paulo. The hippocampus, amygdala, cingulate, and parahipocampal gyri volumes were estimated using FreeSurfer software. We also investigated the association between limbic volumetric measurements, symptom´s severity, and early life stress history (measure by Early Trauma Inventory - ETI). RESULTS: Subjects with PTSD presented reduced volume of the right rostral part of the anterior cingulate, compared to subjects without PTSD, after controlling for intracranial volume, ETI, and depressive symptoms. Subjects with PTSD presented larger bilateral hippocampus and right amygdala, but secondary to the higher ETI. In PTSD group there was a positive correlation between ETI with bilateral hippocampus, bilateral amygdala, and left parahippocampus. LIMITATIONS: First, the cross-sectional study design precludes causal interpretation of limbic structure reduction in PTSD, consequence of PTSD, or other life events. Finally, since the sample size was not sufficiently large, we could not observe whether or not limbic structure volume could be related to the type of trauma. CONCLUSIONS: The present study provides evidence of a reduced anterior cingulate volume in subjects with PTSD than in resilient subjects exposed to urban violence. Enlargement of hippocampus and amygdala volume was observed in subjects with PTSD, however secondary to early trauma experience.

Cerebellar volume in patients with dementia.

OBJECTIVE: The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. METHOD: Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. RESULTS: The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. CONCLUSION: This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis.

Cerebellar volume in patients with dementia / Volume cerebelar em pacientes com demência

OBJECTIVE: The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. METHOD: Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. RESULTS: The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. CONCLUSION: This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis.

OBJETIVO: O objetivo deste estudo foi examinar o volume cerebelar em indivíduos em diferentes fases da doença de Alzheimer e investigar se sua redução estaria relacionada com o declínio cognitivo. MÉTODO: Noventa e seis indivíduos de um estudo epidemiológico foram submetidos à ressonância magnética e avaliados por meio do Mini Exame do Estado Mental e do Questionário de Atividades Funcionais. Os sujeitos foram divididos em cinco grupos de acordo com a Escala de Gravidade da Demência. Vinte e seis indivíduos do grupo original que não tinham o diagnóstico de demência no início do estudo foram reavaliados após dois anos para detectar o desenvolvimento da doença. RESULTADOS: Os volumes dos hemisférios cerebelares, lobo cerebelar posterior, vermis e lobo temporal estavam diminuídos proporcionalmente à gravidade da doença. Houve correlações positivas e significativas entre o Questionário de Atividades Funcionais, Mini Exame do Estado Mental e seus respectivos subtestes para linguagem e atenção com os volumes dos lobos temporal e cerebelar. A análise de regressão logística demonstrou que o volume reduzido do lobo temporal, lobo cerebelar posterior e vermis pode ser um fator de risco para o futuro desenvolvimento de demência. CONCLUSÃO: Este é o primeiro estudo que demonstrou que o volume do cerebelo pode estar reduzido na fase pré-demência e reforça o papel dessa estrutura na progressão da doença de Alzheimer. Considerando que o cerebelo pode não estar diretamente associado com a origem da doença de Alzheimer, este achado tem valor para o prognóstico.

Neurostructural imaging findings in children with post-traumatic stress disorder: brief review.

Child maltreatment has been associated with different psychiatric disorders. Studies on both animals and humans have suggested that some brain areas would be directly affected by severe psychological trauma. The pathophysiology of post-traumatic stress disorder (PTSD) appears to be related to a complex interaction involving genetic and environmental factors. Advanced neuroimaging techniques have been used to investigate neurofunctional and neurostructural abnormalities in children, adolescents, and adults with PTSD. This review examined structural brain imaging studies that were performed in abused and traumatized children, and discusses the possible biological mechanisms involved in the pathophysiology of PTSD, the implications and future directions for magnetic resonance imaging (MRI) studies. Published reports in refereed journals were reviewed by searching Medline and examining references of the articles related to structural neuroimaging of PTSD. Structural MRI studies have been performed in adults and children to evaluate the volumetric brain alterations in the PTSD population. In contrast with studies involving adults, in which hippocampus volumetric reduction was the most consistent finding, studies involving children and adolescents with PTSD have demonstrated smaller medial and posterior portions of the corpus callosum.

Cerebellum and psychiatric disorders.

OBJECTIVE: The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders. METHOD: A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" and "attention deficit hyperactivity disorder". The electronic search was done up to April 2008. DISCUSSION: Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease. CONCLUSION: Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.

Cerebellum and psychiatric disorders / O cerebelo e os transtornos psiquiátricos

OBJECTIVE: The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders. METHOD: A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" and "attention deficit hyperactivity disorder". The electronic search was done up to April 2008. DISCUSSION: Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease. CONCLUSION: Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.

OBJETIVO: Este artigo de atualização tem como objetivo avaliar estudos em neuroimagem estrutural e funcional a fim de explorar o papel do cerebelo na patofisiologia dos transtornos psiquiátricos. MÉTODO: Uma revisão não sistemática foi realizada através do Medline utilizando-se como parâmetro os seguintes termos: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" e "attention deficit hyperactivity disorder". A busca eletrônica foi feita até abril de 2008. DISCUSSÃO: Anormalidades cerebelares estruturais e funcionais têm sido relatadas em muitos transtornos psiquiátricos, entre eles a esquizofrenia, transtorno bipolar, transtorno depressivo, transtornos ansiosos, demências e transtorno de déficit de atenção e hiperatividade. Estudos utilizando imagem por ressonância magnética estrutural relataram a diminuição do volume total do cerebelo e do vermis cerebelar na esquizofrenia, transtornos do humor e transtorno de falta de atenção com hiperatividade. Estudos utilizando ressonância magnética funcional e paradigmas cognitivos têm demonstrado alterações na atividade cerebelar na esquizofrenia, transtornos ansiosos e transtorno de falta de atenção com hiperatividade. Nas demências, o cerebelo é afetado nos estágios mais avançados dessas doenças. CONCLUSÃO: Contrastando com as primeiras teorias, o cerebelo parece apresentar um papel mais importante em diferentes funções cerebrais além do controle motor e do equilíbrio, incluindo a regulação emocional e cognição. Futuros estudos são necessários para melhor elucidar o papel do cerebelo em ambos os comportamentos, normal e patológico, na regulação do humor e nas funções cognitivas.