Anxiety Disorders: Mello MF

Mendes DD, Mello MF, Ventura P, Passarela Cde M, Mari Jde J. · Universidade Federal de São Paulo, Departamento de Psiquiatria, Brazil. · Int J Psychiatry Med. · Pubmed #19069570 No free full text.

Abstract: OBJECTIVE: Cognitive behavioral therapy (CBT) is the most common psychotherapy approach for the treatment of PTSD. Nevertheless, previous reviews on the efficacy of several types of psychotherapy were unable to detect differences between CBT and other psychotherapies. The purpose of this study was to conduct systematic review on the efficacy ofCBT in comparison with studies that used other psychotherapy techniques. METHOD: Databases were searched using the following terms: posttraumatic stress disorder/stress disorder, treatment/psychotherapy/behavior cognitive therapy, randomized trials, and adults. Randomized clinical trials published between 1980 and 2005 and that compared CBT with other treatments for PTSD was included. The main outcomes were remission, clinical improvement, dropout rates and changes in symptoms. RESULTS: The 23 clinical trials included in the review comprised 1923 patients: 898 in the treatment group and 1,025 in the control group. CBT had better remission rates than EMDR (RR = 0.35; 95% CI: 0.16; 0.79; p = 0.01) or supportive therapies (RR = 0.43; 95% CI: 0.25; 0.74; p = 0.002, completer analysis). CBT was comparable to Exposure Therapy (ET) (RR = 0.90; 95% CI: 0.58; 1.40; p = 0.64), and cognitive therapy (CT) (RR = 1.01; 95% CI: 0.67; 1.51; p = 0.98) in terms of efficacy and compliance. CONCLUSIONS: These findings suggest that specific therapies, such as CBT, exposure therapy and cognitive therapy are equally effective, and more effective than supportive techniques in the treatment of PTSD.

Braga LL, Fiks JP, Mari JJ, Mello MF. · Graduate Program in Psychiatry - Department of Psychiatry, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil. · BMC Psychiatry. · Pubmed #18694520 links to  free full text

Abstract: BACKGROUND: Several terms in the scientific literature about posttraumatic stress disorder are used with different meanings in studies conducted by different authors. Words such as trauma, violence, catastrophe, disaster and barbarism are often used vaguely or confusingly, and their meanings change in different articles. The lack of conceptual references for these expressions complicates the organization of literature. Furthermore, the absence of clear concepts may be an obstacle to clinical treatment because the use of these words by the patients does not necessarily point to a diagnosis of posttraumatic stress disorder. DISCUSSION: A critical review of scientific literature showed that stress can be divided in stages to facilitate specific terminological adjustments to the event itself, to the subject-event interaction and to psychological responses. Moreover, it demonstrated that the varying concept of trauma expands into fundamental psychotherapeutic definitions and that the meanings of violence associated with barbarism are an obstacle to resilience. Therefore, this study updates the etymological origins and applications of these words, connects them to the expansions of meanings that can be operated in the clinical care of patients with posttraumatic stress disorder, and analyzes them critically according to the criterion A of DSM-IV and ICD-10. SUMMARY: The terminology in the literature about posttraumatic stress disorder includes a plethora of terms whose meanings are not fully understood, and that, therefore, limit this terminology. The analysis of these terms suggested that the transformation of the concept of trauma led to a broader understanding of this phenomenon in its psychic dimensions, that a barbarian type of violence constitutes an obstacle to resilience, and that the criterion A of the DSM-IV and ICD-10 shows imprecision and conceptual fragilities. METHODS: To develop this debate article, a current specialized literature review was achieved by searching and retrieving the key terms from two major databases: PubMed and PsycINFO. The key terms included "disaster", "catastrophe", "barbarism", "terrorism", "trauma", "psychic trauma" and "violence", also in combination with the terms "PTSD", "concept" and "conceptual aspects". The data were captured specially from review articles. The included studies were those mostly identified by the authors as relevant by the presence of a conceptual approach in any part of the paper. Researches that relied solely on empirical indicators, like psychopathological, neurobiological or pharmacological aspects, were excluded. The focus here was in conceptual aspects, even when some few empirical studies were included. As it was noted a paucity of medical references related to conceptual aspects of these terms, a wider literature needed to be included, including chapters, books and articles proceeded from the Humanities areas. "Interdisciplinary research is needed in this area to include perspectives from a range of different disciplines" once that "to promote public health (...) new dimensions of such interactions and the implications thereof should be pursued in collaboration with researchers from broader areas" 1.

Ruiz JE, Barbosa Neto J, Schoedl AF, Mello MF. · Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brazil. · Rev Bras Psiquiatr. · Pubmed #17546347 links to  free full text

Abstract: OBJECTIVE: To review the literature on neurobiological findings related to hypothalamic-pituitary-adrenal axis dysfunctions associated with posttraumatic stress disorder. METHOD: The relevant scientific findings were described according to the date of publication and the characteristics of the studies: preclinical studies, studies on early life violence as a risk factor, and clinical findings related to patients diagnosed with posttraumatic stress disorder. RESULTS: A rich literature on hypothalamic-pituitary-adrenal axis dysfunctions and posttraumatic stress disorder was found. Neurobiological findings showed that posttraumatic stress disorder is associated with hypothalamic-pituitary-adrenal axis dysfunctions and other brain-related structures: prefrontal cortex, hippocampus, and amygdala. Posttraumatic stress disorder patients have low plasma levels of cortisol and present increased responsivity of glucocorticoid receptors, suggesting that the inhibition of negative feedback plays a significant role in the disorder pathology. Preclinical studies using animal models of maternal deprivation showed that depending on the moment the trauma occurred during the development, different hypothalamic-pituitary-adrenal axis dysfunctions were produced. Clinical studies showed that early life stress is related to the development of psychopathologies during adulthood. CONCLUSIONS: There is robust evidence of hypothalamic-pituitary-adrenal axis dysfunctions related to posttraumatic stress disorder, and the mechanisms underlying this association are being better understood.

Mello AA, Mello MF, Carpenter LL, Price LH. · Butler Hospital, Department of Psychiatry and Human Behavior, Brown Medical School, Rhode Island, USA. · Rev Bras Psiquiatr. · Pubmed #15328550 links to  free full text

Abstract: Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology.

Carpenter LL, Schecter JM, Tyrka AR, Mello AF, Mello MF, Haggarty R, Price LH. · Mood Disorders Research Program, Butler Hospital, Brown Medical School, 345 Blackstone Boulevard, Providence, R.I. 02906, USA. · J Clin Psychiatry. · Pubmed #16426090 No free full text.

Abstract: OBJECTIVE: Gamma-aminobutyric acid (GABA) plays a key role in the pathophysiology and treatment of depression and anxiety. Tiagabine, a selective GABA reuptake inhibitor (SGRI) that enhances normal GABA tone, was evaluated for its efficacy and safety in the treatment of depression comorbid with significant anxiety. METHOD: In this 8-week, single-center, open-label study, adults with DSM-IV-diagnosed major depressive disorder and significant anxiety (i.e., "anxious depression") received tiagabine monotherapy, initiated at 4 mg/day and titrated for optimum response as tolerated to a maximum dose of 20 mg/day. Symptoms, function, and adverse events were assessed at regular intervals. Patients were entered from April 2002 to February 2003. RESULTS: Nineteen patients entered the study and 15 met criteria for intent-to-treat analyses. Of those, 6 (40%) discontinued treatment and 9 (60%) completed the 8-week protocol. Tiagabine significantly improved depression, as shown by a reduction in mean +/- SD Hamilton Rating Scale for Depression scores from baseline (31.9 +/- 6.1) to endpoint (17.0 +/- 12.4; p = .002). Categorical response rate was 47% (N = 7). Tiagabine also significantly improved anxiety (Hamilton Rating Scale for Anxiety baseline score of 22.7 +/- 4.9 vs. endpoint score of 12.5 +/- 8.8; p = .002). The mean +/- SD final daily dose was 12.8 +/- 5.8 mg. The most commonly reported adverse events were dizziness, headache, and gastrointestinal upset/nausea. CONCLUSION: These results suggest the potential of the SGRI tiagabine in the treatment of depression with anxiety. Large, placebo-controlled trials are needed.

Andreoli SB, Ribeiro WS, Quintana MI, Guindalini C, Breen G, Blay SL, Coutinho ES, Harpham T, Jorge MR, Lara DR, Moriyama TS, Quarantini LC, Gadelha A, Vilete LM, Yeh MS, Prince M, Figueira I, Bressan RA, Mello MF, Dewey ME, Ferri CP, Mari Jde J. · Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil. · BMC Psychiatry. · Pubmed #19500422 links to  free full text

Abstract: BACKGROUND: violence is a public health major concern, and it is associated with post-traumatic stress disorder and other psychiatric outcomes. Brazil is one of the most violent countries in the world, and has an extreme social inequality. Research on the association between violence and mental health may support public health policy and thus reduce the burden of disease attributable to violence. The main objectives of this project were: to study the association between violence and mental disorders in the Brazilian population; to estimate the prevalence rates of exposure to violence, post-traumatic stress disorder, common metal disorder, and alcohol hazardous use and dependence: and to identify contextual and individual factors, including genetic factors, associated with the outcomes. METHODS/DESIGN: one phase cross-sectional survey carried out in Sao Paulo and Rio de Janeiro, Brazil. A multistage probability to size sampling scheme was performed in order to select the participants (3000 and 1500 respectively). The cities were stratified according to homicide rates, and in Sao Paulo the three most violent strata were oversampled. The measurements included exposure to traumatic events, psychiatric diagnoses (CIDI 2.1), contextual (homicide rates and social indicators), and individual factors, such as demographics, social capital, resilience, help seeking behaviours. The interviews were carried between June/2007 February/2008, by a team of lay interviewers. The statistical analyses will be weight-adjusted in order to take account of the design effects. Standardization will be used in order to compare the results between the two centres. Whole genome association analysis will be performed on the 1 million SNP (single nucleotide polymorphism) arrays, and additional association analysis will be performed on additional phenotypes. The Ethical Committee of the Federal University of Sao Paulo approved the study, and participants who matched diagnostic criteria have been offered a referral to outpatient clinics at the Federal University of Sao Paulo and Federal University of Rio de Janeiro.

Bressan RA, Quarantini LC, Andreoli SB, Araújo C, Breen G, Guindalini C, Hoexter M, Jackowski AP, Jorge MR, Lacerda AL, Lara DR, Malta S, Moriyama TS, Quintana MI, Ribeiro WS, Ruiz J, Schoedl AF, Shih MC, Figueira I, Koenen KC, Mello MF, Mari JJ. · Laboratório Interdisciplinar de Neurosciencias Clínicas - LiNC, São Paulo, Brazil. · BMC Psychiatry. · Pubmed #19480721 links to  free full text

Abstract: BACKGROUND: Life trauma is highly prevalent in the general population and posttraumatic stress disorder is among the most prevalent psychiatric consequences of trauma exposure. Brazil has a unique environment to conduct translational research about psychological trauma and posttraumatic stress disorder, since urban violence became a Brazilian phenomenon, being particularly related to the rapid population growth of its cities. This research involves three case-control studies: a neuropsychological, a structural neuroimaging and a molecular neuroimaging study, each focusing on different objectives but providing complementary information. First, it aims to examine cognitive functioning of PTSD subjects and its relationships with symptomatology. The second objective is to evaluate neurostructural integrity of orbitofrontal cortex and hippocampus in PTSD subjects. The third aim is to evaluate if patients with PTSD have decreased dopamine transporter density in the basal ganglia as compared to resilient controls subjects. This paper shows the research rationale and design for these three case-control studies. METHODS AND DESIGN: Cases and controls will be identified through an epidemiologic survey conducted in the city of São Paulo. Subjects exposed to traumatic life experiences resulting in posttraumatic stress disorder (cases) will be compared to resilient victims of traumatic life experiences without PTSD (controls) aiming to identify biological variables that might protect or predispose to PTSD. In the neuropsychological case-control study, 100 patients with PTSD, will be compared with 100 victims of trauma without posttraumatic stress disorder, age- and sex-matched controls. Similarly, 50 cases and 50 controls will be enrolled for the structural study and 25 cases and 25 controls in the functional neuroimaging study. All individuals from the three studies will complete psychometrics and a structured clinical interview (the Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD Scale, Beck Anxiety Inventory, Beck Depression Inventory, Global Assessment of Function, The Social Adjustment Scale, Medical Outcomes Study 36-Item Short-Form Health Survey, Early Trauma Inventory, Clinical global Impressions, and Peritraumatic Dissociative Experiences Questionnaire). A broad neuropsychological battery will be administered for all participants of the neuropsychological study. Magnetic resonance scans will be performed to acquire structural neuroimaging data. Single photon emission computerized tomography with [(99m)Tc]-TRODAT-1 brain scans will be performed to evaluate dopamine transporters. DISCUSSION: This study protocol will be informative for researchers and clinicians interested in considering, designing and/or conducting translational research in the field of trauma and posttraumatic stress disorder.

Mello MF, Yeh MS, Barbosa Neto J, Braga LL, Fiks JP, Mendes DD, Moriyama TS, Valente NL, Costa MC, Mattos P, Bressan RA, Andreoli SB, Mari JJ. · Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil. · BMC Psychiatry. · Pubmed #19480669 links to  free full text

Abstract: BACKGROUND: Topiramate might be effective in the treatment of posttraumatic stress disorder (PTSD) because of its antikindling effect and its action in both inhibitory and excitatory neurotransmitters. Open-label studies and few controlled trials have suggested that this anticonvulsant may have therapeutic potential in PTSD. This 12-week randomized, double-blind, placebo-controlled clinical trial will compare the efficacy of topiramate with placebo and study the tolerability of topiramate in the treatment of PTSD. METHODS AND DESIGN: Seventy-two adult outpatients with DSM-IV-diagnosed PTSD will be recruited from the violence program of Federal University of São Paulo Hospital (UNIFESP). After informed consent, screening, and a one week period of wash out, subjects will be randomized to either placebo or topiramate for 12 weeks. The primary efficacy endpoint will be the change in the Clinician-administered PTSD scale (CAPS) total score from baseline to the final visit at 12 weeks. DISCUSSION: The development of treatments for PTSD is challenging due to the complexity of the symptoms and psychiatric comorbidities. The selective serotonin reuptake inhibitors (SSRIs) are the mainstream treatment for PTSD, but many patients do not have a satisfactory response to antidepressants. Although there are limited clinical studies available to assess the efficacy of topiramate for PTSD, the findings of prior trials suggest this anticonvulsant may be promising in the management of these patients. TRIAL REGISTRATION: NCT 00725920.

Mello MF, Costa MC, Schoedl AF, Fiks JP. · Victims of Violence and Stress Program, Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, SP, Brazil. · Rev Bras Psiquiatr. · Pubmed #19142413 links to  free full text

Abstract: OBJECTIVE: Post traumatic stress disorder is frequent in the general population (7.8%-lifetime-USA). The selective serotonin reuptake inhibitors are the first choice of treatment but result in low remission rates. This study aims to evaluate the effect of aripiprazole monotherapy for the treatment of post traumatic stress disorder. METHOD: Thirty-two patients diagnosed with post traumatic stress disorder were included in a 16-week open label trial of aripiprazole. They were evaluated at baseline, week 8, and 16 with the Clinician-Administered PTSD Scale, Beck Depression Inventory, Beck Anxiety Inventory, Medical Outcome Study Short Form 36, and Social Adjustment Scale. Statistical analysis were performed with an intention-to-treat approach and last observation carried forward. A general linear model for repeated measures comparing the factor with 3 continuous measures from baseline, 8 and 16 weeks was used. A between-subject factor was included RESULTS: Nine patients discontinued the treatment. The mean aripiprazole dose was 9.6 (+/- 4.3) mg/day. The mean scores at baseline and endpoint for all measures were: Clinician-Administered PTSD Scale - 82.7 (+/- 23.1) and 51.4 (+/- 31.4) (F = 11.247, p = 0.001); Beck Anxiety Inventory - 31.7 (+/- 13.4) and 25.4 (+/- 18.2) (F = 8.931, p = 0.011); Social Adjustment Scale - 2.4 (+/- 0.45) and 2.27 (+/- 0.57) (F = 8.633, p = 0.012); Medical Outcome Study Short Form 36 - 76.6 (+/- 14.11) and 94.01 (+/- 25.06) (F = 10.127 p = 0.007); and Beck Depression Inventory - 26.06 (+/- 11.6) and 21.35 (+/- 12.6) (F = 1.580, p = 0.042). In all measurements, the differences were statistically significant. CONCLUSIONS: Patients achieved a good response to treatment with aripiprazole, but placebo-controlled studies are needed for more accurate results.

Rikhye K, Tyrka AR, Kelly MM, Gagne GG, Mello AF, Mello MF, Price LH, Carpenter LL. · Mood Disorders Research Program, Butler Hospital, Department of Psychiatry and Human Behavior, Brown Medical School, 345 Blackstone Boulevard., Providence, RI 02906, USA. · Child Abuse Negl. · Pubmed #18082260 No free full text.

Abstract: OBJECTIVE: The aim of this study was to examine associations between childhood adversity, parental bonding, gender, depressive symptoms, and quality of life in non-treatment-seeking adults from the community. METHOD: Effects of differential parental rearing were compared in adults who reported a high degree of childhood maltreatment (n=72) and those who reported no significant adverse events in childhood (n=69). Subjects completed retrospective measures of childhood maltreatment and perceived parenting style, as well as measures of current depressive symptoms and quality of life. RESULTS: The subjects without childhood maltreatment were younger and endorsed less current depressive symptomatology than did subjects with childhood maltreatment. While the subjects without a history of maltreatment reported more "optimal" bonding experiences with their parents, the maltreatment group members were more likely to characterize their early parental bonding experiences in terms of "affectionless control" (p<.001 for both maternal and paternal parenting), "affectionate constraint" (p=.025 for maternal parenting and p=.004 for paternal parenting), or "weak or absent" bonding (p<.001 for both maternal and paternal parenting). Results of a multiple regression analysis revealed that overall quality of paternal care (p=.015) and current level of depressive symptoms (p<.001) were significant independent predictors of adult quality of life. Gender effects between subjects providing parental bonding data were limited to the group with childhood maltreatment. CONCLUSION: These findings extend previous work documenting a relationship between early life maltreatment and suboptimal parental bonding, suggesting gender-specific effects of maternal and paternal care. Effects of childhood maltreatment on quality of life in adulthood appear to be linked with the quality of childhood paternal care and the occurrence of depressive symptomatology in adulthood, suggesting possible targets for primary or secondary prevention.

Carpenter LL, Carvalho JP, Tyrka AR, Wier LM, Mello AF, Mello MF, Anderson GM, Wilkinson CW, Price LH. · Mood Disorders Research Program, Butler Hospital, Brown Medical School, Providence, Rhode Island 02906, USA. · Biol Psychiatry. · Pubmed #17662255 links to  free full text

Abstract: BACKGROUND: Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with major depressive disorder and posttraumatic stress disorder. METHODS: Plasma adrenocorticotropin hormone (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (n = 50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL) (n = 23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL) (n = 27). RESULTS: Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group x time effect characterized the relatively blunted ACTH response of the MAL group. Emotional neglect (-.34, p = .02) and sexual abuse (.31, p = .03) strongly predicted maximal cortisol release. CONCLUSIONS: In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.

Tyrka AR, Mello AF, Mello MF, Gagne GG, Grover KE, Anderson GM, Price LH, Carpenter LL. · Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Butler Hospital, 345 Blackstone Road, Providence, RI 02906, USA. · Psychoneuroendocrinology. · Pubmed #16908106 No free full text.

Abstract: BACKGROUND: Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. METHODS AND MATERIALS: Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). RESULTS: Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. CONCLUSIONS: These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.