Browsing by Author "Stein D.J."
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- Item1H-MRS in autism spectrum disorders: A systematic meta-analysis(2012) Ipser J.C.; Syal S.; Bentley J.; Adnams C.M.; Steyn B.; Stein D.J.We conducted a systematic review and metaanalysis of proton magnetic resonance spectroscopy (1HMRS) studies comparing autism spectrum disorder (ASD) patients with healthy controls, with the aim of profiling ASD-associated changes in the metabolites N-acetylaspartate (NAA) and Creatine (Cr). Meta-regression models of NAA and Cr levels were employed, using data from 20 eligible studies (N0852), to investigate age-dependent differences in both global brain and region-specific metabolite levels, while controlling for measurementmethod (Cr-ratio versus absolute concentrations). Decreased NAA concentrations that were specific to children were found for whole-brain grey and white matter. In addition, a significant decrease in NAA was evident across age categories in the parietal cortex, the cerebellum, and the anterior cingulate cortex. Higher levels of Cr were observed for ASD adults than children in global grey matter, with specific increases for adults in the temporal lobe and decreased Cr in the occipital lobe in children. No differences were found for either NAA or Cr in the frontal lobes. These data provide some evidence that ASD is characterized by age-dependent fluctuations in metabolite levels across the whole brain and at the level of specific regions thought to underlie ASD-associated behavioural and affective deficits. Differences in Cr as a function of age and brain region suggests caution in the interpretation of Cr-based ratio measures of metabolites. Despite efforts to control for sources of heterogeneity, considerable variability in metabolite levels was observed in frontal and temporal regions, warranting further investigation. © Springer Science+Business Media, LLC 2012.
- Item5-HT2A: Its role in frontally mediated executive function and related psychopathology(2007) Stein D.J.; Hemmings, Sian M. J.; Moolman-Smook H.; Audenaert K.Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.
- ItemA comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder.(2006) Warwick, James M.; Carey P.; Van der Linden G.; Prinsloo C.; Niehaus D.; Seedat S.; Dupont P.; Stein D.J.INTRODUCTION: The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT). METHODS: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response. RESULTS: Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide. CONCLUSION: Both SSRI's and RIMA's decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.
- ItemA proteomic analysis of the ventral hippocampus of rats subjected to maternal separation and escitalopram treatment(2009) Marais L.; Hattingh S.M.; Stein D.J.; Daniels W.M.U.Early life stress is known to predispose humans to the development of depression. Developmental stress has been shown to cause various changes in neurotransmitter systems, neurotrophin expression and the hypothalamic pituitary adrenal-axis in the rat brain. The aim of this study was to identify which cytosolic proteins are altered by maternal separation, as a model for depression, as well as by chronic antidepressant treatment. Rats were maternally separated from postnatal day 2-14 for 3 h per day while control rats were normally reared. Both groups were divided and received either escitalopram or saline injections for 6 weeks starting from postnatal day 40. The ventral hippocampal tissue was fractionated and the cytosolic fraction used for 2-D-gel electrophoresis and liquid chromatography coupled to mass spectrometry analyses to identify peptides. Mascot database searches were done to identify proteins that were differentially expressed between the groups. Proteins that were significantly changed by maternal separation included amongst others: molecular chaperones and proteins related to energy metabolism; neuroplasticity; oxidative stress regulation; and protein metabolism. Treatment with escitalopram, a selective-serotonin reuptake inhibitor, induced changes in a different group of proteins, except for a few involved in energy metabolism and neuroprotective pathways. The results indicate which cytosolic proteins are changed by early life stress and may therefore be involved in the development of depression. © 2009 Springer Science+Business Media, LLC.
- ItemA treatment algorithm for generalised anxiety disorder(2001) Stein D.J.; Seedat S.; Niehaus D.J.N.; Pienaar W.; Emsley R.A.[No abstract available]
- ItemAdjunctive quetiapine for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: A meta-analysis of randomized controlled treatment trials(2006) Fineberg N.A.; Stein D.J.; Premkumar P.; Carey P.; Sivakumaran T.; Vythilingum B.; Seedat S.; Westenberg H.; Denys D.Small studies have shown positive effects from adding a variety of antipsychotic agents in patients with obsessive-compulsive disorder who are unresponsive to treatment with serotonin reuptake inhibitors. The evidence, however, is contradictory. This paper reports a meta-analysis of existing double-blind randomized placebo-controlled studies looking at the addition of the second-generation antipsychotic quetiapine in such cases. Three studies fulfilled the inclusion criteria. Altogether 102 individuals were subjected to analysis using Review Manager (4.2.7). The results showed evidence of efficacy for adjunctive quetiapine (<400 mg/day) on the primary efficacy criterion, measured as changes from baseline in total Yale-Brown Obsessive Compulsive Scale scores (P=0.008), the clinical significance of which was limited by between-study heterogeneity. The mechanism underlying the effect may involve serotonin and/or dopamine neurotransmission. © 2006 Lippincott Williams & Wilkins, Inc.
- ItemAltered prefrontal cortical function during processing of fear-relevant stimuli in pregnancy(2011-05-25) Roos A.; Robertson F.; Lochner C.; Vythilingum B.; Stein D.J.In non-pregnant individuals, the prefrontal cortex (PFC) is involved in the regulation of emotion, and appears to play a role in anxiety. Near-infrared spectroscopy (NIRS) detects cortical neural activation without harmful radiation making it safe for use in pregnancy. The aims of this study were to assess neural circuitry involved in processing fear-relevant stimuli during pregnancy using NIRS, and to determine associations between activation of this circuitry, distress and anxiety symptoms, attention to threat, cortisol, estrogen, progesterone and testosterone levels. There was significant activation of the PFC in response to fearful faces compared to rest in both pregnant and control groups. Within pregnancy, the activation was most pronounced at trimester 2, compared to the other trimesters. In pregnant women only (all trimesters), PFC activation was significantly associated with increased distress and anxiety, but with decreased selective attention to masked fear. PFC activation was also significantly associated with increased levels of cortisol and testosterone in pregnancy. PFC function appears to be altered during processing of fear-relevant stimuli in pregnancy. Changes in hormone levels may lead to changes in PFC function, and in turn to changes in cognitive-affective processing and anxiety. Further work is needed, however, to explore precisely how PFC function is altered in pregnancy; it is possible that certain changes reflect altered processing of threat stimuli, while others reflect attempts to compensate for distressing and anxious symptoms that emerge during pregnancy. © 2011 Elsevier B.V.
- ItemAn open trial of citalopram in adolescents with post-traumatic stress disorder(2001) Seedat S.; Lockhat R.; Kaminer D.; Zungu-Dirwayi N.; Stein D.J.In this preliminary, 12-week open-label study, eight adolescents with moderate to severe post-traumatic stress disorder (PTSD) were treated with citalopram the most selective of the selective serotonin reuptake inhibitors) in a fixed daily dose of 20 mg, and rated at 2-week intervals. The Clinician-Administered PTSD Scale (Child and Adolescent Version) was the primary measure used to assess treatment outcome. Core PTSD symptoms (re-experiencing, avoidance, and hyperarousal symptoms) showed statistically significant improvement at week 12 on the Clinician-Administered PTSD Scale (Child and Adolescent Version) (CAPS-CA), with a 38% reduction in total CAPS scores between baseline and endpoint. Citalopram failed to effect improvement on self-reported depressive symptoms. All seven adolescent completers were rated as much improved or very much improved on Clinical Global impression improvement scores. Citalopram was well-tolerated overall with reported adverse experiences being relatively benign. However, larger, controlled trials are needed to consolidate these preliminary, results. © 2001 Lippincott Williams & Wilkins.
- ItemAn open trial of valproate in borderline personality disorder(1995) Stein D.J.; Simeon D.; Frenkel M.; Islam M.N.; Hollander E.Background: Target symptoms in pharmacotherapy of borderline personality disorder include mood instability, anxiety, and impulsivity. Valproate appears useful for the treatment of these target symptoms in several disorders, and carbamazepine has been found effective for such symptoms in borderline personality disorder. We therefore conducted a preliminary open- label trial of valproate in borderline personality disorder. Method: Eleven patients who met DSM-III-R criteria for borderline personality disorder were entered into an 8-week study of valproate. Exclusion criteria included current major depression or major medical disorder. All patients were in psychotherapy at least once a week for a minimum of 8 weeks prior to starting medication. Valproate was increased as tolerated to reach blood levels of 50 to 100 μg/mL. Clinician- and self-rated scales were completed each week. Results: Three patients did not complete the study. Of completers, 4 of 8 patients were responders ('much less' or 'less') on clinician-rated change scores for overall pathology and for mood. Three of 8 patients were responders on change scores for anxiety, anger, impulsivity, and rejection sensitivity. There was a significant (p = .03) decrease in total Symptom Checklist-90 scores between the start and end of the trial. On the Overt Aggression Scale (Modified), total other-directed assault did not significantly decrease, but there was a significant (p = .02) decrease in global subjective irritability. Conclusion: Valproate led to overall improvement in 50% of a small sample of borderline personality disorder patients who completed an 8-week open trial. The medication was modestly helpful for mood and irritability as well as for anxiety, anger, rejection sensitivity, and impulsivity, but specific therapeutic effects varied from patient to patient. More extensive controlled trials of anticonvulsants for impulsive personality disorders are warranted.
- ItemAugmentation of psychotherapy with d-cycloserine for anxiety disorders(2009) Ipser J.C.; Sander C.; Seifan A.; Stein D.J.[No abstract available]
- ItemBarriers to mental health care and predictors of treatment dropout in the South African stress and health study(2011) Bruwer B.; Sorsdahl K.; Harrison J.; Stein D.J.; Williams D.; Seedat S.Objective: This study used data from the South African Stress and Health Study (SASH) to examine both structural and attitudinal barriers to treatment initiation among South Africans with mental disorders and to investigate predictors of treatment dropout. Methods: Face-to-face interviews were conducted with 4,315 adult South Africans living in households or hostel quarters. The interview included a core diagnostic assessment of past-12-month mental disorders and assessments of disorder severity, service use, and barriers to treatment. Multivariate logistic regression models were used to determine predictors of not seeking treatment in relation to disorder severity and sociodemographic characteristics, as well as factors that were predictive of premature treatment discontinuation by participants who had received mental health treatment in the previous 12 months. Predictors of dropout were identified by cross-tabulation and discrete-time survival analysis. Results: Of the 4,315 adults, 729 (16.9% weighted) met criteria for a mental disorder in the past 12 months. Across all levels of severity, the most frequently cited reason for not seeking professional treatment was a low perceived need for treatment. Among those who recognized the need but did not access treatment during the past 12 months (7.2%), attitudinal barriers to treatment seeking were reported more commonly than structural barriers (100% and 34%, respectively). Of the 182 respondents who received treatment (25% weighted), 20% discontinued prematurely. Various factors, such as substance use disorders and absence of health insurance, increased the odds of treatment dropout. Conclusions: Low rates of treatment seeking and high treatment dropout rates for common mental disorders among South Africans are a major concern. Public health efforts to improve treatment of mental disorders should consider the multiple influences on treatment initiation and discontinuation.
- ItemBeauty and the beast: Psychobiologic and evolutionary perspectives on body dysmorphic disorder(2006) Stein D.J.; Carey P.D.; Warwick J.Body dysmorphic disorder (BDD) is characterized by preoccupation with a defect in appearance. Concepts of beauty play a particularly crucial role in humans' mental and social life, and may have specific psychobiologic and evolutionary underpinnings. In particular, there is a growing literature on the neurocircuitry underpinning the body schema, body image and facial expression processing, and aesthetic and symmetry judgments. Speculatively, disruptions in cognitive-affective processes relevant to judgments about physical beauty lead to BDD.
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- ItemChanges in regional brain volumes in social anxiety disorder following 12 weeks of treatment with escitalopram(2010) Cassimjee N.; Fouche J.-P.; Burnett M.; Lochner C.; Warwick, James M.; Dupont P.; Stein D.J.; Cloete K.J.; Carey P.D.It has been suggested that antidepressants, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12-weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific. © 2010 Springer Science+Business Media, LLC..
- ItemCharacterization of South African Adolescents With Alcohol Use Disorders but Without Psychiatric or Polysubstance Comorbidity(2011-05-25) Ferrett H.L.; Cuzen N.L.; Thomas K.G.F.; Carey P.D.; Stein D.J.; Finn P.R.; Tapert S.F.; Fein G.Background: Individuals who begin drinking during early adolescence and exhibit externalizing pathology and disinhibitory/dysregulatory tendencies are more vulnerable to developing alcohol use disorders (AUDs) in adulthood. Previous research has focused on in-treatment populations with substantial comorbid psychopathology and polysubstance use. Here, we characterize a unique sample of treatment-naïve adolescents without such comorbidity to help identify vulnerable youth who may benefit from early intervention. Methods: We compared externalizing propensity, disinhibitory characteristics, and school performance in adolescents with AUDs (but without comorbid psychopathology or other substance use; n=70) to those of demographically matched controls (n=70). Within the AUD group, we compared measures of substance use and the disinhibitory syndrome between boys and girls with differing severity of externalizing propensity. Results: Adolescents with AUDs demonstrated more externalizing propensity and disinhibitory personality traits (impulsivity, novelty seeking, and excitement seeking), poorer self-monitoring and response inhibition, more bullying and sexual risk-taking behavior, poorer first-language performance, and greater use of alcohol, cannabis, and nicotine (p<0.05). Within the AUD group, participants with higher externalizing propensity began drinking earlier, more frequently, and for a longer duration than those with lower externalizing symptoms (p<0.05). Disinhibitory features (personality, cognition, and behavior) were, however, not stronger in those with higher externalizing propensity. Conclusions: We suggest that the constructs of externalizing propensity and disinhibitory syndrome are useful in characterizing treatment-naïve adolescents with AUDs but without comorbid psychopathology or polysubstance use. These results support the importance of these constructs in understanding adolescent AUDs, even when the frank externalizing diagnoses of childhood (oppositional defiant disorder and conduct disorder) are excluded. Copyright © 2011 by the Research Society on Alcoholism.
- ItemCitalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder(2001) Montgomery S.A.; Kasper S.; Stein D.J.; Hedegaard K.B.; Lemming O.M.Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder (OCD). This double-blind, placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors, citalopram, in OCD. A total of 401 patients were randomized to receive citalopram 20, 40 or 60 mg/day or placebo for 12 weeks. All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) change score (P < 0.01). The highest response rate, defined as 25% improvement in Y-BOCS entry score, was observed in the 60 mg group (65%). This compared with 52% and 57.4% in the 40 mg and 20 mg groups. Response rate on placebo was 36.6% (P < 0.05 for all three doses of citalopram compared to placebo). There was no significant difference between the individual doses of citalopram. An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo (P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities). Citalopram was well tolerated; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events. © 2001 Lippincott Williams & Wilkins.
- ItemCognitive-affective neuroscience of somatization disorder and functional somatic syndromes: Reconceptualizing the triad of depression-anxiety-somatic symptoms(2008) Stein D.J.; Muller J.Somatization disorder is a somatoform disorder that overlaps with a number of functional somatic syndromes and has high comorbidity with major depression and anxiety disorders. Proposals have been made for revising the category of somatoform disorders, for simplifying the criteria for somatization disorder, and for emphasizing the unitary nature of the functional somatic syndromes in future classifications. A review of the cognitive-affective neuroscience of somatization disorder and related conditions suggests that overlapping psychobiological mechanisms mediate depression, anxiety, and somatization symptoms. Particular genes and environments may contribute to determining whether symptoms are predominantly depressive, anxious, or somatic, and there are perhaps also overlaps and distinctions in the distal evolutionary mechanisms that produce these symptoms.
- ItemComorbid obsessive-compulsive personality disorder in obsessive-compulsive disorder (OCD): A marker of severity(2011) Lochner C.; Serebro P.; Van der Merwe, L.; Hemmings, Sian M. J.; Kinnear C.; Seedat S.; Stein D.J.Introduction: Comorbid obsessive-compulsive personality disorder (OCPD) is well-described in obsessive-compulsive disorder (OCD). It remains unclear, however, whether OCPD in OCD represents a distinct subtype of OCD or whether it is simply a marker of severity in OCD. Materials and methods: The aim of this study was to compare a large sample of OCD subjects (n = 403) with and without OCPD on a range of demographic, clinical and genetic characteristics to evaluate whether comorbid OCPD in OCD represents a distinct subtype of OCD, or is a marker of severity. Results: Our findings suggest that OCD with and without OCPD are similar in terms of gender distribution and age at onset of OC symptoms. Compared to OCD. -OCPD (n = 267, 66%), those with OCD. +. OCPD (n = 136, 34%) are more likely to present with the OC symptom dimensions which reflect the diagnostic criteria for OCPD (e.g. hoarding), and have significantly greater OCD severity, comorbidity, functional impairment, and poorer insight. Furthermore there are no differences in distribution of gene variants, or response to treatment in the two groups. Conclusion: The majority of our findings suggest that in OCD, patients with OCPD do not have a highly distinctive phenomenological or genetic profile, but rather that OCPD represents a marker of severity. © 2011 Elsevier Inc.
- ItemComorbidity in generalized anxiety disorder: Impact and implications(2001) Stein D.J.; Nutt; Ballenger; Davidson; Wittchen; Lecrubier; BorkovecStudying comorbidity may be particularly useful in shedding light on the nature, course, and management of generalized anxiety disorder (GAD). This article reviews the common comorbidities in GAD, their impact on functioning and on medical utilization, and their implications for treatment. Comorbidity in this area is complex in that GAD may be primary (predating other illnesses) or secondary (following other conditions). Nevertheless, studies demonstrate the high prevalence of patients with a matrix of anxious-somatic-depressive symptoms and show that GAD comorbidity is associated with both increased disability and increased medical utilization. Clinical implications of this work include the need for rigorous assessment of anxiety, somatic, and depressive symptoms in patients who present with any one of these sets of complaints and the possibility that early treatment of GAD may be critical in preventing subsequent morbidity.