Cognitive control associated with irritability induction: an autobiographical recall fMRI study.

OBJECTIVE: Despite the relevance of irritability emotions to the treatment, prognosis and classification of psychiatric disorders, the neurobiological basis of this emotional state has been rarely investigated to date. We assessed the brain circuitry underlying personal script-driven irritability in healthy subjects (n = 11) using functional magnetic resonance imaging. METHOD: Blood oxygen level-dependent signal changes were recorded during auditory presentation of personal scripts of irritability in contrast to scripts of happiness or neutral emotional content. Self-rated emotional measurements and skin conductance recordings were also obtained. Images were acquired using a 1,5T magnetic resonance scanner. Brain activation maps were constructed from individual images, and between-condition differences in the mean power of experimental response were identified by using cluster-wise nonparametric tests. RESULTS: Compared to neutral scripts, increased blood oxygen level-dependent signal during irritability scripts was detected in the left subgenual anterior cingulate cortex, and in the left medial, anterolateral and posterolateral dorsal prefrontal cortex (cluster-wise p-value < 0.05). While the involvement of the subgenual cingulate and dorsal anterolateral prefrontal cortices was unique to the irritability state, increased blood oxygen level-dependent signal in dorsomedial and dorsal posterolateral prefrontal regions were also present during happiness induction. CONCLUSION: Irritability induction is associated with functional changes in a limited set of brain regions previously implicated in the mediation of emotional states. Changes in prefrontal and cingulate areas may be related to effortful cognitive control aspects that gain salience during the emergence of irritability.

Validity of a frustration-induction procedure.

OBJECTIVE: To test a reliable and easily administered frustration-induction procedure for experimental research. METHOD: One hundred volunteers (81 women, mean age +/- SD 34.2 +/- 8 years) physically and psychiatrically healthy submitted to the frustration induction procedure were prevented from reaching reward level scores. Subjective aggressiveness feelings related to frustration were self-rated in a 13-item visual analogue scale before and after the procedure. RESULTS: Significant increases in aggressiveness-related feelings were detected in 12 of the 13 items. This was consistent with the observed overt behavior of the subjects during the task. CONCLUSIONS: The frustration-induction procedure is a simple, easy to administer frustration-induction procedure that can be used in experimental studies in normal subjects.

Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode.

BACKGROUND: Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience. Brain Derived Neurotrophic Factor (BDNF) gene has been considered an important candidate marker for the development of bipolar disorder and this neurotrophin seems involved in intracellular pathways modulated by mood stabilizers. Also, previous studies demonstrated a role for BDNF in the pathophysiology and clinical presentation of mood disorders. METHODS: We investigated whether BDNF levels are altered during mania. Sixty subjects (14 M and 46 F) were selected and included in the study. Thirty patients meeting SCID-I criteria for manic episode were age and gender matched with thirty healthy controls. Young Mania Rating Scale (YMRS) evaluated the severity of manic episode and its possible association with the neurotrophin levels. RESULTS: Mean BDNF levels were significantly decreased in drug free/naive (224.8 +/- 76.5 pg/ml) compared to healthy controls (318.5 +/- 114.2), p < .001]. Severity of the manic episode presented a significant negatively correlation to plasma BDNF levels (r= .78; p < .001; Pearson test). CONCLUSIONS: Overall, these results suggest that the decreased plasma BDNF levels may be directly associated with the pathophysiology and severity of manic symptoms in BD. Further studies are necessary to clarify the role of BDNF as a putative biological marker in BD.

Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects.

Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.

Dopamine genes and pathological gambling in discordant sib-pairs.

Pathological gambling (PG) is an impulse control disorder that has been considered as a behavioral addiction. Recent studies have suggested the involvement of the dopaminergic system in addictions and impulse control disorders and associations of dopamine receptor genes (DRD1, DRD2, and DRD4) and PG have been reported. In the present study, 140 sib-pairs discordant for the diagnosis of PG (70 males and 70 females on each group) were recruited through the Gambling Outpatient Unit at the Institute of Psychiatry, University of Sao Paulo and were assessed by trained psychiatrists. A family-based association design was chosen to prevent population stratification. All subjects were genotyped for dopamine receptor genes (DRD1 -800 T/C, DRD2 TaqIA RFLP, DRD3 Ser9Gly, DRD4 48bp exon III VNTR, DRD5 (CA) repeat) and the dopamine transporter gene (SCL6A3 40 bp VNTR). Our results suggest the association of PG with DRD1 -800 T/C allele T (P = .03).

Pathological gambling and obsessive-compulsive disorder: towards a spectrum of disorders of volition.

OBJECTIVE: Pathological gambling is proposed as a participant of an impulsive-compulsive spectrum related to obsessive-compulsive disorder. This study aims to contrast pathological gambling and obsessive-compulsive disorder regarding course, comorbidity, and personality, hence testing the validity of the impulsive-compulsive spectrum. METHOD: 40 pathological gambling and 40 obsessive-compulsive disorder subjects matched to 40 healthy volunteers according to gender, age, and education were assessed with the Temperament Personality Questionnaire and the Barratt Impulsiveness Scale. Psychiatric patients were also assessed for course and comorbidity data. RESULTS: Obsessive-compulsive disorder presented an earlier onset, but the full syndrome took longer to evolve. Pathological gambling had higher comorbidity with substance-related disorders, and obsessive-compulsive disorder higher comorbidity with somatoform disorders. Gamblers scored higher than controls on the sub-factors Impulsiveness, Extravagance, Disorderliness, and Fear of Uncertainty. Obsessive-compulsive patients scored higher than controls on Fear of Uncertainty. Impulsiveness, Extravagance, and Disorderliness significantly correlated with the Barratt Impulsiveness Scale total score, Fear of Uncertainty did not. DISCUSSION: The course and comorbidity profiles of pathological gambling resemble an addiction and differ from obsessive-compulsive disorder. Pathological gambling combines impulsive and compulsive traits. Impulsivity and compulsivity should be regarded as orthogonal constructs, and as drives implicated in volition aspects of behavioral syndromes.

Factors at play in faster progression for female pathological gamblers: an exploratory analysis.

BACKGROUND: Previous studies reported a faster progression for alcohol dependence and pathological gambling among females as compared with males. This phenomenon was called the "telescoping effect." By comparing female gamblers with male gamblers regarding gambling preferences and comorbidity, the authors explored potential risk factors for telescoping. METHOD: A consecutive sample of Brazilian treatment-seeking pathological gamblers (DSM-IV criteria) was recruited. Genders were contrasted regarding comorbidity and gambling behavior, controlling for demographics, gambling severity, and previous access to mental health services. RESULTS: Seventy female gamblers and 70 male gamblers were interviewed. A greater proportion of women than men reported electronic bingo and video lottery terminals as their main type of gambling. Gambling was divided in 3 progressive stages: "social gambling," "intense gambling," and "problem gambling." Faster progression for female gamblers was confirmed; female gender and preference for electronic bingo and/or video lottery terminals were risk factors for telescoping throughout all stages. Female gamblers presented a higher comorbidity with depression, whereas male gamblers had higher rates of alcohol dependence. Nevertheless, comorbidity profiles were not related to gambling progression. CONCLUSION: Two factors could be at play for treatment-seeking female gamblers in Brazil: (1) a potential gender vulnerability and (2) a cultural environment yielding them access to a narrower range of gambling games that includes mainly the most addictive ones.

Pathological gambling, gender, and risk-taking behaviors.

Seventy-eight female and 78 male pathological gamblers admitted to an outpatient treatment program were compared regarding a profile of risk-taking behaviors (suicide attempts, illegal activities meant to finance gambling, sexual risky behavior, and alcohol abuse). The Schedules for Clinical Assessment in Neuropsychiatry (SCAN), the Barratt Impulsiveness Scale version 11 (BIS-11), and an adaptation of the HIV Risk Behavior Scale were used. Females attempted more suicide than males. Men had more sexual risky behavior and alcohol abuse than women. Younger age and depression were risk factors for suicide attempts, younger age and impulsivity were risk factors for illegal activities. Younger age was a risk factor for sexual risky behavior, and no risk factor other than male gender was found for alcohol abuse. Future investigation of risk behaviors among gamblers must take into account the differences in gender and age. Both impulsivity and emotional distress are related to risk-taking in gamblers, and young gamblers who early in life display other potentially harmful behaviors require special attention.

Family-based association analysis of serotonin genes in pathological gambling disorder: evidence of vulnerability risk in the 5HT-2A receptor gene.

Pathological gambling (PG) has become a growing public health problem in many countries around the world. PG is an impulse control disorder and its behavior and psychopathology present similarities with substance abuse disorders. Evidence from twin studies supports a significant genetic predisposition to PG, but the precise genetic loci still remain unclear. The present study investigates the allele and genotype distribution of polymorphisms of the serotonin transporter, serotonin receptor 1B and 2A genes in 140 sib-pairs discordant for the diagnosis of PG. A significant association of the C/C genotype of the serotonin receptor 2A T102C (rs 6313) polymorphism and the PG phenotype was observed [OR = 1.7 (1.1-3.4)]. This preliminary result is consistent with the hypothesis that the serotonin system is associated with addiction behavior and similar results have been reported for nicotine and alcohol dependence.

Dentin decalcification during lithium treatment: case report.

Severe dental decay and changes in tooth structure have been reported in association with the use of lithium in Psychiatry, but lithium effects on tooth inorganic composition remain unknown. A 30-year-old woman with bipolar disorder, treated with lithium carbonate presented severe dental decay. Dentin samples from lithium and healthy volunteers were collected and submitted to ionic and ultrastructural analysis. Samples from the lithium patient exhibited irregular peritubular walls and the mineral crystals were irregularly arranged in the intertubular dentin. In addition, a decrease in Mg/P/Ca and an increase of Zn concentrations were detected. These data suggest that the severe dental decay and changes in the tooth structure observed for the lithium-treated patient are related to dentin mineral loss and that this pathological condition is different from caries lesions.

Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study.

The objective of this international, 8-week, randomized, double-blind study was to show the superiority of the antidepressant efficacy of agomelatine, the first MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, versus fluoxetine in outpatients fulfilling Diagnostic and Statistical Manual of Mental Disorders-volume IV-TR criteria for major depressive disorder of severe intensity, defined by a baseline Hamilton Depression Rating Scale (HAM-D17) total score of at least 25 and CGI severity of illness score of at least 4. Patients received agomelatine 25-50 mg/day (n=252) or fluoxetine 20-40 mg/day (n=263) for 8 weeks. The main efficacy outcome measure was HAM-D17 total score (change from baseline to last post-baseline assessment). Secondary outcome measures were Clinical Global Impressions-improvement (CGI), severity (CGI-S), anxiety (HAM-A), and sleep (HAM-D sleep items) scores. The mean decrease in HAM-D17 total score over 8 weeks was significantly greater with agomelatine than fluoxetine with a between-group difference of 1.49 (95% confidence interval, 0.20-2.77; P=0.024). The percentage of responders at last post-baseline assessment was higher with agomelatine on both HAM-D17 (decrease in total score from baseline ≥50%; 71.7% agomelatine vs. 63.8% fluoxetine; P=0.060) and CGI-improvement (score 1 or 2; 77.7 vs. 68.8%; P=0.023). There was a significant between-group difference of 0.37 (95% confidence interval, 0.06-0.68) in HAM-D sleep subscore in favor of agomelatine (P=0.018). Similar improvements were observed on HAM-A with agomelatine and fluoxetine. Both treatments were safe and well tolerated. In conclusion, in this study, agomelatine showed superior antidepressant efficacy over fluoxetine in treating patients with a severe episode of major depressive disorder after 8 weeks of treatment with a good tolerability profile.

Bipolar disorder and concurrent psychiatric and medical disorders.

A correct diagnosis of bipolar disorder is crucial to determining appropriate treatment strategies, but the majority of patients with this illness are initially misdiagnosed. Bipolar presentations share features with other psychiatric disorders such as unipolar depression and borderline personality disorder, and comorbid medical conditions further complicate diagnosis. Clinicians may minimize diagnostic and treatment issues by focusing on differential diagnosis and dual treatment of bipolar disorder and co-occurring conditions. The physical health of patients with bipolar disorder should be monitored, because this population is at risk for obesity, metabolic syndrome, and associated conditions.

Introduction to bipolar disorder and comorbid conditions.

Bipolar disorder presents with symptoms that overlap with other, often comorbid, psychiatric disorders, such as borderline personality disorder, substance use disorder, and unipolar depression, and also often co-occurs with medical disorders. Appropriate screening for manic and hypomanic symptoms may lessen the frequency of misdiagnosis of bipolar disorder as unipolar depression, which has serious treatment implications. Further, following the appropriate guidelines for monitoring the physical health of patients with bipolar disorder, especially those treated with mood stabilizers and atypical antipsychotic agents, is important to achieve optimal outcomes.

Effect of chronic treatment with clomipramine on food intake, macronutrient selection and body weight gain in rats.

Long-term treatment with clomipramine (CMI), a tricyclic antidepressant, induces food craving and body weight gain in patients. The present study investigated the effects of chronic treatment with CMI on total food intake, macronutrient selection, and body weight gain in rats. Male Wistar rats were maintained on a dietary self-selection regime with separate sources of protein, fat and carbohydrate. Animals received i.p. injections of CMI (0, 3, 10, 30 mg/kg) during 27 consecutive days. Food consumption and body weight were recorded daily and results were calculated as average of three consecutive days, namely during pre-treatment (3 d before pharmacological treatment), treatment (7th-9th; 16th-18th and 25th-27th days), and post-treatment (28th-33rd days). Results showed that CMI (30 mg/kg) significantly decreased energy intake during all treatment period, an effect that was related to a decrease in both carbohydrate-rich diet intake and body weight gain. At dose of 3 mg/kg CMI increased the total energy intake in the 16th-18th days, suggesting an apparent biphasic effect of chronic treatment with CMI on caloric intake. Chronic administration with CMI (27 d) did not alter protein-rich or fat-rich diet consumption. The main result of this study indicated that chronic treatment with CMI decreases rather than increase food consumption and body weight gain in rats exposed to a macronutrient self-selection procedure.

Cognitive control associated with irritability induction: an autobiographical recall fMRI study / Controle cognitivo associado à indução de irritabilidade: um estudo de RMf usando recordações autobiográficas

OBJECTIVE: Despite the relevance of irritability emotions to the treatment, prognosis and classification of psychiatric disorders, the neurobiological basis of this emotional state has been rarely investigated to date. We assessed the brain circuitry underlying personal script-driven irritability in healthy subjects (n = 11) using functional magnetic resonance imaging. METHOD: Blood oxygen level-dependent signal changes were recorded during auditory presentation of personal scripts of irritability in contrast to scripts of happiness or neutral emotional content. Self-rated emotional measurements and skin conductance recordings were also obtained. Images were acquired using a 1,5T magnetic resonance scanner. Brain activation maps were constructed from individual images, and between-condition differences in the mean power of experimental response were identified by using cluster-wise nonparametric tests. RESULTS: Compared to neutral scripts, increased blood oxygen level-dependent signal during irritability scripts was detected in the left subgenual anterior cingulate cortex, and in the left medial, anterolateral and posterolateral dorsal prefrontal cortex (cluster-wise p-value < 0.05). While the involvement of the subgenual cingulate and dorsal anterolateral prefrontal cortices was unique to the irritability state, increased blood oxygen level-dependent signal in dorsomedial and dorsal posterolateral prefrontal regions were also present during happiness induction. CONCLUSION: Irritability induction is associated with functional changes in a limited set of brain regions previously implicated in the mediation of emotional states. Changes in prefrontal and cingulate areas may be related to effortful cognitive control aspects that gain salience during the emergence of irritability.

OBJETIVO: Apesar da relevância de emoções de irritabilidade para o tratamento, prognóstico e classificação dos transtornos psiquiátricos, as bases neurobiológicas deste tipo de estado emocional foram raramente investigadas até hoje. Este estudo avaliou os circuitos cerebrais subjacentes à irritabilidade induzida por scripts pessoais em voluntários saudáveis (n = 11) usando ressonância magnética funcional. MÉTODO: Mudanças no sinal dependente do nível de oxigenação sanguínea (blood-oxygen level dependent signal) foram registradas durante a apresentação por via auditiva de scripts pessoais de irritabilidade em contraste com scripts de felicidade ou de conteúdo emocional neutro. Escores em escalas de autoavaliação emocional e medidas de condutância da pele também foram obtidos. A aquisição de imagens foi realizada em aparelho de ressonância magnética de 1,5 T. Os mapas de ativação cerebral foram construídos a partir das imagens individuais, e as diferenças entre as condições experimentais foram investigadas utilizando testes não-paramétricos baseados em permutações. RESULTADOS: Em comparação com scripts neutros, a apresentação de scripts de irritabilidade levou a aumentos de sinal dependente do nível de oxigenação sanguínea na porção subgenual do giro do cíngulo anterior esquerdo e nas porções medial, ântero-lateral e póstero-lateral do córtex pré-frontal dorsal (cluster-wise p-valor < 0,05). Enquanto o envolvimento do cíngulo anterior subgenual e do córtex pré-frontal dorsal antero-lateral surgiu apenas em associação com o estado de irritabilidade, aumentos do sinal dependente do nível de oxigenação sanguínea nas porções dorso-medial e dorsal póstero-lateral do córtex pré-frontal também estiveram presentes durante indução de felicidade. CONCLUSÃO: Indução de irritabilidade está associada a mudanças de atividade funcional num conjunto restrito de regiões cerebrais previamente implicadas na mediação de estados emocionais. Mudanças na atividade...

Prevalence of ICD-10 mental disorders in a catchment area in the city of São Paulo, Brazil.

BACKGROUND: The prevalence (lifetime, 12-month, 1-month) of mental disorders, their relationship with sociodemographic features, and the use of services were investigated in the population aged 18 years or older living in the catchment area of a large hospital complex in the city of São Paulo, Brazil. METHODS: A community survey was conducted in two boroughs of São Paulo, on 1,464 residents aged 18 years or older. The assessment of psychopathology was made by CIDI 1.1, yielding diagnoses according to ICD-10 for mood disorders, anxiety disorders, non-affective psychosis, substance use disorders, dissociative and somatoform disorders, and cognitive impairment. RESULTS: Of the total sample, 45.9 % had at least one lifetime diagnosis of mental disorder, 26.8 % in the year, and 22.2 % in the month prior to interview. The most prevalent disorders (lifetime, 12-month, and 1-month, respectively) were: nicotine dependence (25 %, 11.4 %, 9.3 %), any mood disorder (18.5 %, 7.6 %, 5 %) with depressive episode the most prevalent mood disorder (16.8 %, 7.1 %, 4.5 %), any anxiety disorder (12.5 %, 7.7 %, 6 %), somatoform disorder (6 %, 4.2 %, 3.2 %), and alcohol abuse/dependence (5.5 %, 4.5 %, 4 %). No gender differences were found in overall morbidity. Excluding substance use disorders, women had a higher risk for non-psychotic disorders. The presence of psychiatric diagnosis increased the use of services, with a low proportion of subjects seeking specialty mental care. CONCLUSION: Our results confirm the high prevalence of mental disorders in the community, similar to findings in other countries. A comparison with findings from other studies with similar methodology is made.