Browsing by Author "Ipser, Jonathan"

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    An investigation of amygdala and hippocampal subregions and their relation to ageing in anxiety and related disorders
    (2024) Ntwatwa, Ziphozihle; Ipser, Jonathan; Groenewold, Nynke; Stein, Dan; van Honk, Jack
    Background Obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) are debilitating disorders that are associated with (inconsistent) evidence of hippocampal and amygdala volumetric abnormalities. In addition, both OCD and SAD are associated with accentuated biological aging, as indexed by cellular and molecular markers. Nevertheless, little is known about brain aging in OCD and SAD, or the extent to which inconsistencies in hippocampal and amygdala volume findings in these disorders may be due to the differential effect of age on the subfields from which these structures are composed. Accordingly, this dissertation set out to characterise differences in hippocampal and amygdala subfield volumes between healthy controls (HCs) and participants with OCD and SAD in large-scale MRI datasets and relate these to whole and regional brain aging. Methods Hippocampal and amygdala subfield volumes and brain age estimates were derived from T1 weighted MRI images from the OCD Brain Imaging Consortium (De Wit et al., 2014) and the European and South African Research Network in Anxiety Disorders (Bas-Hoogendam et al., 2017). Subfield volumes were segmented using an automated segmentation algorithm from Freesurfer (v6.0). The brain age analysis was performed by using a previously trained machine learning algorithm that provides brain age estimates for the whole brain, as well as for regions of interest (occipital, frontal, temporal, parietal, cingulate, insula, or cerebellar–subcortical features) (Kaufmann et al., 2019). Differences in relative brain age (brain predicted age difference; brain-PAD) were calculated by subtracting chronological age from the predicted brain age. Between-group differences (diagnosis vs HCs) in volumetric and brain-PAD estimates were assessed using a mixed-effects (d) model adjusted for several covariates. Subgroup analyses were performed to determine the association of the main findings with clinical characteristics. Finally, unique associations between subfield volumes and whole brain age were estimated using partial correlation analysis. Results There was no evidence for a difference in subfield volumes between individuals with OCD and HCs. However, we found that psychotropic medication use was associated with significantly smaller hippocampal dentate gyrus (d=-0.26, pFDR=0.042), molecular layer (d=-0.29, pFDR=0.042) and larger lateral (d=0.23, pFDR=0.049) and basal (d=0.25, pFDR=0.049) amygdala subfields than HCs. Individuals with OCD without psychotropic medication use had significantly smaller hippocampal CA1 (d=-0.28, pFDR=0.016) compared to HCs. No association was found for symptom severity. In contrast to the findings for OCD, individuals with SAD demonstrated significantly smaller basal (d= 0.32, pFDR=0.022), accessory basal (d=-0.42, pFDR=0.005) and corticoamygdaloid transition area (d=0.37, pFDR=0.014) amygdala subfields overall compared to HCs, and larger hippocampal CA3 (d=0.34, pFDR=0.024), CA4 (d=0.44, pFDR= 0.007), dentate gyrus (d=0.35, pFDR= 0.022) and molecular layer (d=0.28, pFDR=0.033). In addition, individuals with SAD without comorbid anxiety disorder had smaller lateral amygdala and hippocampal amygdala transition area, compared to HCs. No association was found for psychotropic medication use and symptom severity. Individuals with OCD (n=375) had significantly higher whole brain-PAD (+1.6 years, pFDR=0.006, d=0.20) compared to HCs (n=335), but no differences were observed in the regional models. The effect on whole brain brain-PAD estimates was largely driven by psychotropic medication use as higher relative brain age was evident in individuals with OCD with psychotropic medication use (+2.98 years, d=0.38, p <0.001) compared to HCs, but not in individuals without psychotropic medication use (+0.57 years, d=0.07, p =0.374) compared to HCs. No association was found for symptom severity. Partial correlation analysis found a significant negative association between hippocampal and amygdala volume and whole brain PAD in the OCD group (R=-0.224, p=0.00001), but not in the HC group (R=0.081, p=0.138), specifically the lateral nucleus (R=-0.18), CAT(R=-0.13), hippocampal fimbria (R=0.17), and hippocampal fissure (R=0.17) were significant in OCD. Individuals with SAD (n=107) had significantly higher whole brain-PAD (+2.5 years, d=0.33, pFDR=0.010) compared to HCs (n=137), and significantly higher regional brain-PAD in the temporal (+3.80 years, d=0.37, pFDR=0.008,), parietal (+3.57 years, d=0.38, pFDR=0.008), occipital (+3.26 years, d = 0.33, pFDR=0.010), and frontal regions (+2.97 years, d=0.33, pFDR=0.010,) compared to HCs. Brain PAD was higher in SAD without comorbid anxiety disorder, without MDD, and without psychotropic medication use. No association was found for symptom severity. There was no partial correlation between subfields and brain age. Discussion & Conclusion The evidence presented in the thesis suggests that 1) differences in subfield volumes between OCD and HCs were influenced by psychotropic medication use, which is consistent with previous studies that suggest that psychotropic medication status is a strong confounder for subcortical brain volumes observed in OCD, 2) differences in subfield volumes between SAD and HCs were observed in the areas associated with sensory information processing and these differences were partially influenced by psychiatric comorbidity, 3) both OCD and SAD were associated with accentuated brain aging with differential patterns in the whole and regional brain, dependent on clinical characteristics, and 4) only OCD relative brain age was associated with subfield volumes. It is unclear whether our findings in OCD and SAD reflect an adaptive response or are a pre-existing risk factor to these disorders, or both. Future longitudinal analysis is required to investigate whether the observed differences in subfield volume and brain age remain over time.
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    Cognitive therapy, working memory training, and the treatment of Methamphetamine Use Disorder - a functional MRI study
    (2020) Dias, Angelo Ridge; Ipser, Jonathan; Brooks, Samantha
    Background: In recent years, methamphetamine use disorder (MUD), which is associated with adverse outcomes and represents a significant public health burden, has become highly prevalent in Cape Town, South Africa. Protracted methamphetamine (MA) use has been linked with neural dysfunction and working memory deficits. Although current treatments have shown limited efficacy in addressing MUD, recent evidence indicates the potential of utilizing tailored brief cognitive therapy programs and working memory training to improve outcomes. The current study aims to investigate the potential impact of brief cognitive therapy and using working memory training as an adjunct in the treatment of MUD. Methods: Participants were recruited from an in-patient drug rehabilitation centre in Cape Town. The sample (n = 26) consists of male patients (between the ages of 18–50) diagnosed with MUD. MUD patients were randomly split into 2 groups that received 4 weeks of treatment, i.e. treatment as usual (cognitive therapy only (NT) (n= 12)) and cognitive therapy with working memory training (CT) (n = 14). Neuroimaging and psychological data were collected from participants pre- and post- intervention to assess the relative impact of said interventions. Results: Behavioural outcome measures and the n-back working memory task adapted for fMRI were measured and compared pre- and post- intervention. No significant differences were present between groups prior treatment on behavioural measures, demographic measures, and fMRI activity. The brief cognitive therapy appeared to reduce depression and impulsivity scores over the course of the intervention, with scores slightly lower in the CT group. An FDR corrected whole-brain repeated measures ANOVA on the main effect of group indicated significant activation in the left posterior cingulate, left anterior cingulate, and left lingual gyrus. Post hoc t-tests were then conducted to follow up the group main effect and significant differences under FDR correction were observed in the NT group (in contrast to the CT group) indicating significantly more activity in the left superior temporal gyrus, left insula, right posterior declive, and right lingual gyrus. Significant differences were also observed under FDR correction on a posthoc test on the CT group (in contrast to the NT group) indicating significantly less activity in the left lingual gyrus, left posterior declive, and right cuneus. 5 Conclusions: The findings tentatively suggest that the working memory training adjunct may have slightly enhanced working memory maintenance brain function relative to the treatment as usual group post-intervention. The evidence also suggests that there may have been inefficient neural functioning in the treatment as usual group during the working memory task compared to the group receiving the working memory training adjunct. The results demonstrated that brief cognitive therapy treatment did somewhat reduce depressive symptoms and impulsivity in this study, with indications of subtle treatment gains in the cognitive training group. Overall, the current study (despite numerous limitations) provides preliminary and tentative evidence of the possible benefits of brief term cognitive therapy and the potential promise of using working memory training as a treatment adjunct.
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    Effects of methamphetamine on prenatally exposed children in Cape Town: cognition and intrinsic functional brain connectivity
    (2015) Kwiatkowski, Maja Anna; Thomas, Kevin; Roos, Annerine; Ipser, Jonathan
    Methamphetamine use among pregnant women is an increasing problem in South Africa. The aim of this cross-sectional exploratory study was to examine the possible neurotoxic effects of prenatal methamphetamine exposure (PME) on cognition and the developing brain in a sample of affected children in Cape Town, South Africa. Thus, this is a two-part study: the first part examines the effects of PME on neuropsychological outcomes, and the second part examines the effects of PME on intrinsic functional brain connectivity. Children with PME (n = 23) and unexposed controls (n = 22) completed a battery of neurocognitive assessments, and a smaller sub-sample (n = 36; 19 children with PME, 17 unexposed controls) also underwent resting-state functional magnetic resonance imaging (RS-fMRI). Independent samples t-tests revealed that children with PME scored significantly more poorly on measures of IQ, learning and memory, confrontation naming, visual-motor integration, and fine motor co-ordination, when compared to controls. Hierarchical regression analyses confirmed that PME has a significant effect on cognitive performance, and that this effect largely withstands the effects of potentially confounding sociodemographic and anthropometric variables. Independent component analyses revealed significant betweengroup differences in functional brain networks detected in task-free RS-fMRI in children with PME. Specifically, there is evidence for compromised connectivity within and between the basal ganglia network and default mode network in children with PME. Overall, the findings contribute to the small but growing literature on the cognitive effects of PME. The current study is the first to document preliminary evidence indicating aberrant intrinsic functional brain connectivity in children with PME, and suggests that further investigation of potential associations between particular neurocognitive deficits and such aberrant connectivity might be warranted.
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    Executive function and contingency management for methamphetamine use disorder in South Africa: a comparison pre- and post-treatment
    (2021) van Nunen, Lara Jane; Ipser, Jonathan; Stein Dan
    Background: Methamphetamine dependence is associated with impairment in executive function, as well as brain functional and structural alterations, findings on the relationship between executive function impairment and brain alterations seem inconsistent. Methamphetamine dependence may respond to contingency management, yet it is unclear if the treatment response is predicted by these neuropsychological, and brain functional and structural changes, and whether treatment alters neuropsychological impairment. I first conducted a systematic review to rigorously assess available findings on the relationship between executive function impairment and brain functional changes. I then explored data from a study of contingency management in methamphetamine dependence with the aims of determining 1) whether treatment response was predicted by executive function impairment and brain functional and structural alterations, and 2) whether treatment led to changes in executive function and brain functional and structural impairment in treatment responders and non-responders. Methods: The systematic review involved a rigorous search and assessment of articles on the association of stimulant use and resting state functional connectivity. In the empirical study, 33 subjects underwent executive function testing, resting state-fMRI, and structural neuroimaging prior to contingency management treatment. Executive function was assessed with the trail making task, the Stroop-word task, and the Connors continuous performance task. Seed-based analysis was used for functional MRI, with a focus on brain regions associated with executive function, and brain structural alterations were assessed using measures of cortical thickness and surface area. In the statistical analysis, first associations of baseline executive function, rs-fMRI, and brain structural alterations with treatment outcome were assessed using linear regression, and second, comparison of executive function, rsfMRI, and brain structural parameters at baseline versus at treatment end in treatment responders and non-responders was undertaken using linear regression, Cohen's d and a change score. Results: The systematic review noted specific associations between executive function impairment and resting state-fMRI. While in the study, treatment responders had improved executive function at baseline as assessed by two measures (faster completion times on the trail making, and greater accuracy on the Connors continuous performance task), but worse executive function on a third measure (lower accuracy on the Stroop word task) when compared with non-responders. No statistically significant differences between groups was found with regards to rsFC, however greater cortical thickness was found in responders brain regions associated with executive function, in comparison to non-responders. Analysis of pre vs post treatment findings showed that in treatment responders there was better executive function after treatment, in comparison to non-responders (as assessed by greater accuracy on the Connors continuous performance task). Furthermore, in treatment responders there was greater increase in cortical volume in regions associated with executive function, than in non-responders. Conclusion: These findings support the hypothesis that better executive function at baseline (task switching and selective attention) is associated with better outcomes in a contingency management trial of 8-weeks. There is also evidence of improved executive function post trial (in selective attention and cortical thickness findings support improved executive function) implying that abstinence as a consequence of a contingency management trial of 8-weeks may improve executive function, a larger sample size would be needed to determine if improvements extend to other regions of executive function
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    Hypertext navigation, goal (dis)orientation, and the role of mental models : an empirical investigation
    (2002) Ipser, Jonathan; Bokhorst, Frank
    An exploratory investigation into the capabilities of hypertext as an educational medium was conducted. To this purpose, a model was advanced in an attempt to provide a theoretical foundation for the explication of hypertext navigation and disorientation in terms of relevant user characteristics. 75 2nd year psychology students from the University of Cape Town participated in a study in order to investigate the claim that the motivational theory of goal orientation has the greatest utility in accounting for the exploitation of links within a hypertext, a necessary precondition for the development of mental models which incorporate both the conceptual and structural elements required for effective learning from, and the reduction of disorientation within, this medium. The results obtained, although compromised, provide some support for this argument. The paper concludes with a discussion of the methodological limitations of the study, as well as possible directions for future research.
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    Intrinsic functional brain connectivity in South African methamphetamine users undergoing inpatient treatment, with or without additional cognitive training
    (2021) Banwell, Michelle Jeanne; Ipser, Jonathan
    Background: Methamphetamine (MA) abuse is a global crisis that exacerbates sociopolitico-economic burdens in South Africa. MA use is associated with a myriad of neural abnormalities of structure and function, with associated neurocognitive deficits, particularly executive function (EF). Working memory (WM) training has been identified as a potential adjunct to treatment of substance use disorder (SUD) to improve EF in the hope of reducing relapse rates. Neuroimaging suggests MA alters intrinsic resting state functional connectivity (rsFC), and this may contribute to neuropsychological deficits observed in methamphetamine use disorder (MUD). Methods: This nested study analysed data described in Brooks et al. (2016), in which WM training was used as an adjunct to inpatient treatment of MUD. Healthy controls (HC, N = 25) were compared to two MUD groups, one receiving treatment as usual (TAU, N = 17), and one receiving additional cognitive training (CT, N = 24) in the form of a modified version of the ‘N-back' task (C-Ya). This task was also used to assess WMA in the neural scanner, using conditions of 0-back and 1-back across groups. The current research explored these data in a novel manner through examining rsFC. Hypotheses: It was predicted that: 1) HC and MUD participants would differ on measures of WMA, but WMA would improve in MA groups at follow-up compared to baseline and this would be augmented in the CT group; 2) rsFC networks of neural regions supporting WM would be predictive of ability to perform well and improve on WM tasks; and 3) MA groups would display heightened rsFC activity within and between resting state neural networks of the default mode network (DMN) and canonical cognitive control networks (CCNs). Results: Significant differences were observed between HC and MA groups in race and level of education, but not on WMA as tested in the scanner. The CT group, who completed WMA 3-back conditions, demonstrated significant improvement on this task post- intervention. Exploratory regression models showed the WM rsFC network did not demonstrate significant relationships with any clinical, demographic, or WM variables when controlling for multiple comparisons. Heightened connectivity within and between the DMN and CCNs was observed in the MUD compared to the HC group, which provided support for hypothesis 3. Exploratory multivariate regression models demonstrated race, age, education, duration of drug use, and an interaction of group and abstinence may impact rsFC in these networks. Post-hoc analyses identified pairwise network combinations affected by these variables. Conclusions: Despite limitations of this small study, it offers tentative preliminary insights into the largely unexplored field of rsFC in MA populations. This study supports limited research demonstrating hyperconnectivity within and between CCNs and DMN of MA users. This study also offers support for recent research suggesting that easier conditions of the Nback task may not reliably test all aspects of WM function. Exploratory analyses of covariates potentially affecting rsFC provide a platform for directions of future research.
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    Neuroimaging and neurocognitive assessment of PTSD and MDD in a South African community setting
    (2019) Koopowitz, Sheri; Ipser, Jonathan; Stein, Dan
    Background: There is growing evidence of abnormalities in neurocognition, neuroanatomy, and functional connectivity in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). However, there has been less work on individuals who suffer with comorbid PTSD and MDD. It is important to investigate the neurobiology of this overlap because of its prevalence, its associated morbidity, and the hope that it may shed more light on the mechanisms involved in each disorder, including the role of the prefrontal regions. This dissertation tests the hypothesis that women with PTSD and MDD display distinct patterns of neurocognitive impairment and associated brain dysfunction, relative to healthy controls, and these effects will be amplified in patients with both disorders. Methods: This dissertation was undertaken within the Drakenstein Child Health Study, a study exploring child health determinants in mother-infant dyads from the Drakenstein district, Western Cape. Mothers (between 18 and 50 years) were recruited and divided into 4 groups: PTSD, MDD, PTSD with MDD, and healthy controls. Participants were assessed using the computerised NIH Toolbox, and paper and pencil neurocognitive tests. Domains assessed included memory, learning, and processing speed, and with particular focus on executive function and attention domains. Participants underwent resting-state functional imaging as well as structural brain imaging. Functional connectivity within and between cognitive control networks (salience network, dorsal attention network, and frontoparietal networks) and a default mode network were compared across the 4 groups. Neuroanatomical indices (cortical thickness, volume, and surface area) of 10 frontal cortical regions from the Desikan-Killiany atlas in Freesurfer 6 were analysed across the 4 groups. Results: All three clinical groups demonstrated no group differences on measures of attention and executive function, diagnoses of PTSD and MDD were associated with more intrusive thoughts and delayed recall impairment, respectively. However, neurocognitive findings indicate that PTSD with comorbid MDD is not associated with greater neurocognitive dysfunction relative to mono-diagnostic groups. Abnormal resting-state connectivity was observed for the MDD group in the default mode network, and for both comorbid and MDD patient groups within frontoparietal networks. Abnormal salience network connectivity for the comorbid group was observed when examining performance on the Pattern Comparison Processing Speed test. No between-network connectivity group differences were observed. Surface area and volume reductions of prefrontal regions were evident for PTSD and MDD, however, no volumetric and surface area differences were observed for the comorbid group. Conclusion: In this sample of mothers from a low-middle income region, distinct patterns of neurocognitive dysfunction and impairment in PTSD, MDD, and PTSD with MDD were observed. However, contrary to hypotheses, comorbidity is not associated with greater dysfunction and impairment and the associations of PTSD and comorbid MDD are not amplified in this sample. These findings have implications for the development of treatment plans for patients diagnosed with PTSD, MDD, and PTSD with comorbid MDD, so that interventions are tailored in a way that is responsive to differences between these groups in the presentation of neurocognitive profile, brain function, and structure.
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    Pharmacotherapy for post-traumatic stress disorder - a systematic review and meta-analysis
    (2006) Ipser, Jonathan; Seedat, Soraya; Stein, Dan J
    Background. Post-traumatic stress disorder (PTSD) is a prevalent and disabling condition. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in use of medication in its treatment. Objectives. To assess the effects of medication in the treatment of PTSD. Design. Systematic review of randomised controlled trials (RCTs) following the Cochrane Collaboration guidelines. A more detailed version of the review is published in the Cochrane Database of Systematic Reviews. Methods. We searched the Cochrane Depression, Anxiety and Neurosis Group specialised register, the Cochrane Central Register of Controlled Trials (Cochrane Library issue 4, 2004), MEDLINE (January 1966 - December 2004), PsycINFO (1966 - 2004), the National PTSD Center Pilots database, and the meta register module of the Controlled Trials database. Reference lists of retrieved articles were searched for additional studies. Two raters independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary statistics were stratified by medication class, and by medication agent for the selective serotonin re-uptake inhibitors (SSRIs). Dichotomous and continuous measures were calculated using a random effects model, heterogeneity was assessed, and subgroup/sensitivity analyses were done. Main results. Thirty-five short-term (14 weeks or less) RCTs were included in the analysis (4 597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference (WMD) = −5.76, 95% confidence interval (CI): −8.16 - −3.36, N = 2 507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents compared with placebo (relative risk (RR) = 1.49, 95% CI: 1.28, 1.73, number needed to treat (NNT) = 4.85, N = 1 272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (N = 628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was also effective in reducing the severity of the PTSD re-experiencing/intrusion, avoidance/numbing, and hyperarousal symptom clusters in 9 trials (N = 1 304). In addition, medication was superior to placebo in reducing comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of the 3 maintenance trials suggested that long-term medication may be required in treating PTSD.Conclusion. Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability, and should be considered as part of the treatment of this disorder. The findings of this review support the status of SSRIs as first-line agents in the pharmacotherapy of PTSD, as well as their value in longterm treatment. However, there remain important gaps in the evidence base, and there is a continued need for more effective agents in the management of PTSD.
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    Pharmacotherapy for post-traumatic stress disorder- a systematic review and meta-analysis
    (2006) Ipser, Jonathan; Seedat, Soraya; Stein, Dan J
    Background. Post-traumatic stress disorder (PTSD) is a prevalent and disabling condition. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in use of medication in its treatment. Objectives. To assess the effects of medication in the treatment of PTSD. Objectives. To assess the effects of medication in the treatment of PTSD. Design. Systematic review of randomised controlled trials (RCTs) following the Cochrane Collaboration guidelines. A more detailed version of the review is published in the Cochrane Database of Systematic Reviews. Methods. We searched the Cochrane Depression, Anxiety and Neurosis Group specialised register, the Cochrane Central Register of Controlled Trials (Cochrane Library issue 4, 2004), MEDLINE (January 1966 - December 2004), PsycINFO (1966 - 2004), the National PTSD Center Pilots database, and the meta register module of the Controlled Trials database. Reference lists of retrieved articles were searched for additional studies. Two raters independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary statistics were stratified by medication class, and by medication agent for the selective serotonin re-uptake inhibitors (SSRIs). Dichotomous and continuous measures were calculated using a random effects model, heterogeneity was assessed, and subgroup/sensitivity analyses were done. Main results. Thirty-five short-term (14 weeks or less) RCTs were included in the analysis (4 597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference (WMD) = −5.76, 95% confidence interval (CI): −8.16 - −3.36, N = 2 507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents compared with placebo (relative risk (RR) = 1.49, 95% CI: 1.28, 1.73, number needed to treat (NNT) = 4.85, N = 1 272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (N = 628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was also effective in reducing the severity of the PTSD re-experiencing/intrusion, avoidance/numbing, and hyperarousal symptom clusters in 9 trials (N = 1 304). In addition, medication was superior to placebo in reducing comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of the 3 maintenance trials suggested that long-term medication may be required in treating PTSD. Conclusion. Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability, and should be considered as part of the treatment of this disorder. The findings of this review support the status of SSRIs as first-line agents in the pharmacotherapy of PTSD, as well as their value in longterm treatment. However, there remain important gaps in the evidence base, and there is a continued need for more effective agents in the management of PTSD.
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    Pharmacotherapy for Social Anxiety Disorder and Posttraumatic Stress Disorder: New Meta-Analytic Approaches to Synthesising the Evidence
    (2019) Williams,Taryn Amos; Ipser, Jonathan; Stein, Dan; Cipriani, Andrea
    Background Social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD) are prevalent, disabling and highly comorbid disorders. SAD is the most prevalent of the anxiety disorders, and PTSD is the central disorder in the DSM-5 section on trauma- and stressor-related disorders. Given the growing need to consider the totality of evidence for pharmacological treatment for SAD, the publication of systematic reviews and of novel meta-analytic approaches have become of interest for the use of medication in their treatment and decision making. This dissertation has three objectives 1) To update Cochrane reviews of pharmacotherapy for SAD and PTSD, 2) To conduct a qualitative systematic review of network meta-analyses for pharmacological treatment of common mental disorders, 3) To conduct network meta-analyses for SAD and for PTSD and to compare findings to standard pairwise meta-analytic methods. Methods To obtain eligible trials to answer each aim, trials were identified through a systematic search of a variety of electronic databases: the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References), MEDLINE, EMBASE, PsycINFO, Google Scholar, Scopus, PubMed Central, the International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch), clinicaltrials.gov, the National PTSD Center Pilots database and the metaRegister module [mRCT] of the Controlled Trials database, specific to each aim. RCTs of pharmacological treatments comparing active drug versus active drug or active drug versus placebo for SAD and PTSD were considered for inclusion in the respective chapters, and in answering the aims, with the inclusion of add on trials in the SAD and PTSD NMA reviews. Adult participants (18-65 years) diagnosed with SAD and PTSD according to the Diagnostic Statistical Manual for Mental Disorders (DSM, all versions) were included in the individual reviews (i.e. for chapter two, three, five and six). In chapter three adolescents and adults with common mental disorders (depression, GAD, PD, OCD, PTSD, SAD and specific phobia) diagnosed according to the DSM or the International Classification of Diseases ((ICD- 10) were included. The primary and secondary outcomes across aims and reviews include clinical response rates (i.e. the Clinical Global Impressions Improvement scale (CGI-I) or similar) and acceptability (i.e. dropouts due to side effects); and the investigation of symptom severity for SAD with the Liebowitz Social Anxiety Scale (LSAS) and PTSD with the Clinician Administered PTSD Scale (CAPS). In addition, the proportion of dropouts due to any cause were also assessed. The quality of each trial was assessed according to the Cochrane Risk of Bias Tool. GRADE was also used to grade the quality of evidence for the Cochrane reviews and NMAs and the International Society for Pharmacoeconomics and Outcomes Research checklist of good research practices for indirect treatment-comparison in assessing studies for aim two. For aim one, the extracted data for the SAD and PTSD Cochrane reviews was exported into RevMan 5.3.5. Software, which was used to conduct a meta-analysis for SAD and PTSD separately. Pre-planned subgroup and sensitivity analyses were conducted for each review, as well as the generation of funnel plots to assess publication bias with the Eggers' regression test using the R statistical computing platform for the SAD review. In answering aim three, standard pairwise meta-analyses were performed using a random effects model and Frequentist method in RStudio version 3.5 for the SAD NMA review, and Bayesian method using Markov chain Monte Carlo methods in WinBUGS version 1.4.3 for the PTSD NMA. The P-score, an analogue to the surface under the cumulative ranking curves (SUCRA), was used to rank the treatments on a continuous scale for all pairwise comparisons for the SAD NMA, and for the PTSD review, ranking probabilities using the surface under the cumulative ranking curve (SUCRA) and mean ranks were assessed. Results For aim one, the evidence for the standard pairwise Cochrane reviews of SAD and PTSD were most convincing for the treatment efficacy of SSRIs (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984 and k = 8, RR 1.61; 95% CI 1.41 to 1.84, N = 1078, respectively), and was based on very low quality evidence. Evidence of a benefit for the SSRIs was also observed for the reduction of social anxiety symptoms on the LSAS (k = 14, mean difference (MD) −10.14 points, 95% CI −14.05 to −6.22, N = 1990) and posttraumatic symptoms on the CAPS (k = 14, MD −4.69 points, 95% CI −7.18 to −2.20, N = 2709). Other medications such as SSRIs, the serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine, monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine were also effective in reducing SAD symptoms, with evidence of a treatment response for anticonvulsants with gamma-amino butyric acid (GABA) analogues, the MAOIs, the RIMAs and the benzodiazepines. For the treatment of PTSD, the alpha-blocker prazosin and antipsychotics reduced symptom severity, and the alpha-blocker prazosin and the tricyclic antidepressant amitriptyline improved number of responders. Overall, SSRIs were less well tolerated than placebo in both reviews (SAD Review: k = 5131, RR 2.59; 95% CI 1.97 to 3.39, N = 5131; PTSD Review: (k = 15, RR 1.41; 95% CI 1.07 to 1.87, N = 2493), but there were low absolute rates of withdrawal compared to placebo (16% and 14%, respectively). There were no significant differences in dropouts due to any cause in both reviews for the SSRI intervention arms (SAD Review: k = 26, RR 1.01; 95% CI 0.90 to 1.14, N = 5208; ; PTSD Review: k = 21, RR 1.13; 95% CI 0.93 to 1.38, N = 3206). Twenty NMAs (i.e. investigating depressive disorder, GAD, SAD, PTSD and OCD) were found in answering aim three, and antidepressants were found to be the most efficacious and tolerable agents for these disorders based on rankings (45% of NMAs) or statistical significance (55% of NMAs). The quality of the reporting of each NMA was high. Seventy percent of the NMAs included a network diagram and 75% of the included NMAs assessed consistency, made use of a random effects model, provided information on the model used to fit the data and adjusted for covariates. The review also revealed that few NMAs reported rankings of treatments. The SAD and PTSD NMA provided similar findings to the Cochrane reviews, discussed in aim one. For aim three (the SAD NMA), the SSRI paroxetine was significantly more effective than placebo in reducing the number of responders (odds ratio (OR) 2.64; CI 1.97 to 3.54) and anxiety symptoms (mean difference (MD) -15.89; CI -29.94 to -1.84) yet performed worse in comparison to placebo for dropouts due to adverse events. Most of the medications (i.e.12 out of 19 comparisons) reported a decrease in dropout rates relative to placebo, but no statistically significant difference was found. There was also evidence that venlafaxine is efficacious in treating SAD symptoms. According to the rankings of individual treatments olanzapine performed better than the rest of the treatments in terms of treatment efficacy and buspirone for dropouts due to any cause. Bromazepam performed well in treating the number of responders due to adverse events. Similarly, for the PTSD NMA, paroxetine was also effective in the treatment of PTSD symptoms (MD -15.89; CI -29.94 to -1.84). Evidence was also observed for phenelzine, desipramine and risperidone for the treatment of PTSD symptoms. Mirtazapine yielded a relatively high rank for efficacy, but the respective value for acceptability was not among the best treatments. Most evidence from both NMAs was associated with low to very low-quality evidence. Conclusion Different meta-analytic approaches are useful in presenting, synthesising, and reporting data. The evidence discussed here suggest that SSRIs are effective in the treatment and reduction of SAD and PTSD symptoms, even though the tolerability of SSRIs was lower than placebo for each disorder. It is noteworthy that similar estimates were found across the different approaches to synthesising data and across the different patient groups (i.e. SAD and PTSD). In addition, the NMAs found in this dissertation show high quality of reporting and that study limitations do not impact on the network estimate. The quality of reporting of individual RCTs included across the review however remain low, and so additional research is needed in this area.
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    Piloting a mental health training programme for community health workers in South Africa: an exploration of changes in knowledge, confidence and attitudes
    (BioMed Central, 2018-06-14) Sibeko, Goodman; Milligan, Peter D; Roelofse, Marinda; Molefe, Lezel; Jonker, Deborah; Ipser, Jonathan; Lund, Crick; Stein, Dan J
    Background There is a shortage of trained mental health workers in spite of the significant contribution of psychiatric disorders to the global disease burden. Task shifting, through the delegation of health care tasks to less specialised health workers such as community health workers (CHWs), is a promising approach to address the human resource shortage. CHWs in the Western Cape province of South Africa provide comprehensive chronic support which includes that for mental illness, but have thus far not received standardized mental health training. It is unknown whether a structured mental health training programme would be acceptable and feasible, and result improved knowledge, confidence and attitudes amongst CHWs. Methods We developed and piloted a mental health training programme for CHWs, in line with the UNESCO guidelines; the WHO Mental Health Gap Action Programme and the South African National framework for CHW training. In our quasi-experimental (before-after) cohort intervention study we measured outcomes at the start and end of training included: 1) Mental health knowledge, measured through the use of case vignettes and the Mental Health Knowledge Schedule; 2) confidence, measured with the Mental Health Nurse Clinical Confidence Scale; and 3) attitudes, measured with the Community Attitudes towards the Mentally Ill Scale. Knowledge measures were repeated 3 months later. Acceptability data were obtained from daily evaluation questionnaires and a training evaluation questionnaire, while feasibility was measured by participant attendance at training sessions. Results Fifty-eight CHWs received the training, with most (n = 56, 97.0%) attending at least 7 of the 8 sessions. Most participants (n = 29, 63.04%) demonstrated significant improvement in knowledge, which was sustained at 3-months. There was significant improvement in confidence, along with changes in attitude, indicating improved benevolence, reduced social restrictiveness, and increased tolerance to rehabilitation of the mentally ill in the community but there was no change in authoritarian attitudes. The training was acceptable and feasible. Conclusions Mental health training was successful in improving knowledge, confidence and attitudes amongst trained CHWs. The training was acceptable and feasible. Further controlled studies are required to evaluate the impact of such training on patient health outcomes. Trial registration PACTR PACTR201610001834198 , Registered 26 October 2016.
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    The relationship between impulsivity, affect and a history of psychological adversity: a cognitive-affective neuroscience approach
    (2011) Ipser, Jonathan; Stein, Dan J
    There is increasing evidence that trauma exposure is associated with impulsive behaviour and difficulties regulating affect. The findings of recent studies implicate the disruption of neurobiological mechanisms, particularly those involving the neurotransmitter serotonin, in both impulsivity and affect regulation.
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    The brain age gap in social anxiety disorder
    (2021) Blake, Kimberly Vanessa; Groenewold, Nynke; Ipser, Jonathan; Stein, Dan
    Background: When an individual's brain appears ‘older' than expected based upon their chronological age, they may be at an increased risk for developing brain-related diseases and cognitive decline. There is growing evidence of advanced brain ageing in neuropsychiatric diseases. Social anxiety disorder (SAD) is a disabling mental illness, which has been associated with both structural brain deficits and advanced biological ageing. However, brain age research has yet to be conducted in adults diagnosed with SAD. The present study investigated whether adults with SAD showed an advanced brain ageing process, compared to healthy controls (HCs), and whether brain ageing in SAD patients is associated with clinical characteristics. Method: A systematic review of the literature was conducted to identify knowledge gaps in brain age research in psychiatric disorders before commencing with the present dissertation. Hereafter, a secondary data analysis of a large multi-site dataset was performed. T1-weighted structural MRI scans of 387 participants (SAD n=174, HC n=213) between the ages 18 and 60 years were included. These structural scans were segmented using both FreeSurfer and SPM12, after which they underwent quality control procedures. Brain age was estimated by two different machine learning models – Tobias Kaufmann's brain age model and James Cole's BrainageR. The primary outcome for analysis was the brain age gap (BAG), calculated by subtracting a participants' chronological age from their estimated brain age. General linear models were run to determine whether there was a significantly larger positive BAG in the SAD group (Kaufmann model n=100, Cole model n=155) compared to the HC group (Kaufmann model n=138, Cole model n=197) after adjusting for age, mean centred age2 and sex. The association between BAG and comorbid depression and anxiety, as well as medication use and symptom severity, was also assessed. Results: In the present study sample, predicted age was more strongly associated with chronological age for the Cole model estimates than the Kaufmann model estimates (Cole: Pearson correlation = 0.828, MAE = 4.78, SD = 3.96, versus Kaufmann: Pearson correlation = 0.576, MAE = 11.93, SD = 6.93). With the Kaufmann model, the SAD group had a significantly larger BAG than the HC group of almost one year (mean difference = 0.943 year, SE = 0.40, p = .019). In addition, with the Kaufmann model, patients without psychiatric comorbidities had a significantly larger BAG than HCs, of more than one year (mean difference = 1.242 year, SE = 0.49, p = .038). No difference was observed in BAG between patients with comorbidities and HCs (mean difference = 0.983 year, SE = 0.85, p = .749). In contrast, with the Cole model, the SAD group did not have a significantly larger BAG than the HC group (mean difference = 0.513 year, SE = 0.49, p = .383). Moreover, the Cole model found no significant difference in BAG between SAD patients with and without comorbidities, or between each of these groups and HCs (all p > .708). Finally, no significant associations were observed between the BAG and symptom severity and the BAG and medication use in SAD patients in the Cole or Kaufmann models. Conclusion: This study observed contradictory evidence for a larger BAG between patients with SAD than HCs. The differences observed between the Cole model and the Kaufmann model may be a result of the different information used to estimate brain age (voxel-based volumetric data, compared to cortical thickness/surface area and subcortical/cerebellar volumes, respectively). The models demonstrated largely overlapping confidence intervals for group mean difference in BAG, suggesting that if there is a positive BAG in adults diagnosed with SAD, it is likely to be small. This should be verified in future research by using multiple different machine learning models based on different feature sets, to obtain more reliable and robust brain age estimates.
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    The call for relevance: South African psychology ten years after democracy
    (2004) De la Rey, Cheryl; Ipser, Jonathan
    A number of scholars during the 1980s and early 1990s questioned the relevance of psychology in South Africa. In this paper we characterise the nature of what became known as the ‘relevance debate’, and then investigate whether South African psychology has become more relevant during the nation's first ten years of democracy. Themes which are identified with respect to this issue include the apparent increasing representation of marginalised groups within South African psychology, the conscious responsiveness of psychologists to post-apartheid policy imperatives and issues, their alignment with international theoretical trends, and finally, an increasing recognition of the political nature of South African psychology. The authors conclude that a more productive approach within future debates regarding relevance in psychology would be to examine the nature of knowledge production within the discipline.