Publications by authors named "Lisa Fiksenbaum"

28 Publications

  • Page 1 of 1

Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

J Affect Disord 2021 Jun 28;289:135-143. Epub 2021 Apr 28.

University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

Methods: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

Results: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

Limitations: Cross-sectional design, modest sample size.

Conclusions: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.jad.2021.04.040DOI Listing
June 2021

Clinical and neurostructural characteristics among youth with familial and non-familial bipolar disorder: Family history and youth bipolar disorder.

J Affect Disord 2021 03 29;282:1315-1322. Epub 2020 Dec 29.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON, M6J 1H4, Canada; Department of Psychiatry, University of Toronto, 250 College Street, 8th floor, Toronto, ON, M5T 1R8, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Rm 4207 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. Electronic address:

Background: Bipolar disorder (BD) is highly heritable and often severe, particularly when illness onset occurs early in life. There is limited knowledge regarding the clinical and neurostructural correlates of family history of BD among youth with BD.

Methods: Clinical characteristics were evaluated in 197 youth with BD, ages 13-20 years, including 87 with familial BD and 110 with non-familial BD. Structural neuroimaging was examined in a subsample of familial BD (n=39), non-familial BD (n=42), and healthy control (HC, n=58) youth. Region of interest (ROI) analyses of anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), and amygdala were complemented by whole-brain vertex-wise analyses.

Results: Youth with familial BD had more family history of other psychiatric disorders, less severe worst manic episode, and less treatment with lithium, selective serotonin reuptake inhibitor (SSRI) antidepressants, and any lifetime psychiatric medications. None of these findings survived after correction for multiple comparisons. There were no significant between-group differences in ROI analyses. In whole-brain analyses, significant differences in cortical thickness were as follows: familial and non-familial BD < HC in left precentral gyrus and right inferior parietal lobe; familial BD < HC in left superior frontal gyrus; non-familial BD < HC in right precentral gyrus.

Limitations: Relatives did not complete full diagnostic interviews.

Conclusions: There were relatively few differences in clinical and neurostructural correlates related to family history of BD in youth with BD. Current findings suggest that family history of BD is not a strong contributor to the clinical or neuroimaging phenotypes in youth with BD.
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http://dx.doi.org/10.1016/j.jad.2020.12.146DOI Listing
March 2021

Prevalence and correlates of police contact amongst youth with bipolar disorder.

J Affect Disord 2021 03 2;283:243-248. Epub 2021 Feb 2.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada. Electronic address:

Objectives: While multiple studies have examined prevalence and correlates of police contact in adults with bipolar disorder (BD), literature on this topic in youth is sparse. We therefore examined the prevalence and correlates of police contact amongst youth with BD.

Methods: The study included 197 youth with BD and 127 healthy controls, ages 14-20 years. Semi-structured interviews were used to determine diagnoses, treatment and police contact. The Life Problems Inventory examined self-reported trait impulsivity and emotional dysregulation. Analyses examined demographic and clinical variables among youth with versus without lifetime police contact. Variables that were associated with police contact at p<0.1 in univariate analyses were evaluated in a logistic regression model. Specific reasons for police contact, determined based on chart review, are reported descriptively.

Results: Lifetime prevalence of police contact was significantly higher amongst youth with BD versus healthy controls (36% versus. 3%; χ  = 47.58, p =<0.001). In multivariate analyses, age of BD onset, living with both natural parents, comorbid substance use disorder and conduct disorder, and psychiatric hospitalization were associated with police contact. Common reasons for police contact included shoplifting/theft and suicidality/self-harm .

Limitations: The cross-sectional and retrospective study design precludes conclusions regarding directionality of the observed associations and/or causal inferences.

Conclusions: One third of youth with BD experienced police contact. Correlates generally aligned with those observed with adults. Future longitudinal research is warranted to understand distal and proximal antecedents of police contact, with the goal of developing strategies to prevent police contact, incarceration, and related consequences.
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http://dx.doi.org/10.1016/j.jad.2021.01.078DOI Listing
March 2021

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder.

Acta Psychiatr Scand 2021 Jun 16;143(6):513-525. Epub 2021 Feb 16.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Objective: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth.

Methods: This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association.

Results: There were significant group differences in the association of LDL-C (β = -0.29 p = 0.001), and TC (β = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (β = -0.25 p = 0.01) and area (β = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (β = -0.27 p = 0.007) and reduced HDL-C (β = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex.

Conclusion: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.
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http://dx.doi.org/10.1111/acps.13278DOI Listing
June 2021

Severe anhedonia among adolescents with bipolar disorder is common and associated with increased psychiatric symptom burden.

J Psychiatr Res 2021 02 11;134:200-207. Epub 2020 Dec 11.

Department of Pharmacology, University of Toronto, ON, Canada; Centre for Youth Bipolar Disorder, Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada. Electronic address:

Background: Anhedonia, a deficit in the ability to experience pleasure, is a cardinal symptom of major depressive episodes. In contrast to adolescent major depressive disorder, there is limited research examining anhedonia in the context of depression among adolescents with bipolar disorder (BD). We therefore examined clinical characteristics of anhedonia in a large sample of adolescents with BD.

Methods: Participants were 197 adolescents, aged 13-20 years old, with BD type I, II or not otherwise specified. Diagnoses were determined using a semi-structured interview. Anhedonia severity was rated from one to six on the Depression Rating Scale (DRS). Adolescents were divided into "severe" and "non-severe" anhedonia groups based on the DRS item scoring. The association of anhedonia with clinical and demographic variables was evaluated in univariate analyses followed by logistic regression analyses for variables with p ≤ 0.1.

Results: Threshold anhedonia was evident among 90.9% during their most severe depressive episode. Significant factors associated with severe most severe lifetime anhedonia ("lifetime anhedonia") included: female sex, lifetime history of self-injurious behavior, physical abuse, affective lability, higher lifetime depression severity, comorbid anxiety disorders, family history of ADHD, and second-generation antipsychotic use. In regression analyses, severe lifetime anhedonia was independently associated with female sex, comorbid anxiety disorders, most severe lifetime mania severity, and lifetime second-generation antipsychotic use.

Conclusion: The vast majority of adolescents with BD experience anhedonia. More severe anhedonia is associated with indicators of greater illness severity. Future research is warranted to evaluate the neurobiological underpinnings of anhedonia among adolescents with BD.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.031DOI Listing
February 2021

Neurostructural Correlates of Cannabis Use in Adolescent Bipolar Disorder.

Int J Neuropsychopharmacol 2021 Mar;24(3):181-190

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

Background: Little is known regarding the association of cannabis use with brain structure in adolescents with bipolar disorder (BD). This subject is timely, given expanded availability of cannabis contemporaneously with increased social acceptance and diminished societal constraints to access. Therefore, we set out to examine this topic in a sample of adolescents with BD and healthy control (HC) adolescents.

Methods: Participants included 144 adolescents (47 BD with cannabis use [BDCB+; including 13 with cannabis use disorder], 34 BD without cannabis use [BDCB-], 63 HC without cannabis use) ages 13-20 years. FreeSurfer-processed 3T MRI with T1-weighted contrast yielded measures of cortical thickness, surface area (SA), and volume. Region of interest (amygdala, hippocampus, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) analyses and exploratory vertex-wise analysis were undertaken. A general linear model tested for between-group differences, accounting for age, sex, and intracranial volume.

Results: Vertex-wise analysis revealed significant group effects in frontal and parietal regions. In post-hoc analyses, BDCB+ exhibited larger volume and SA in parietal regions, and smaller thickness in frontal regions, relative to HC and BDCB-. BDCB- had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. There were no significant region of interest findings after correcting for multiple comparisons.

Conclusion: This study found that cannabis use is associated with differences in regional brain structure among adolescents with BD. Future prospective studies are necessary to determine the direction of the observed association and to assess for dose effects.
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http://dx.doi.org/10.1093/ijnp/pyaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968618PMC
March 2021

Clinical and neuroimaging correlates of cardiorespiratory fitness in adolescents with bipolar disorder.

Bipolar Disord 2021 May 30;23(3):274-283. Epub 2020 Sep 30.

Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.

Introduction: Cardiovascular disease (CVD) is exceedingly prevalent, and occurs prematurely in individuals with bipolar disorder (BD). Cardiorespiratory fitness (CRF), arguably the most important modifiable CVD risk factor, is also associated with brain structure and function. There is a gap in knowledge regarding CRF in BD, particularly in relation to brain structure.

Methods: Adolescents with BD (n = 54) and healthy controls (HC; n = 53) completed semi-structured diagnostic interviews, self-report questionnaires, and 20 minutes of cardiorespiratory exercise at 60-80% of estimated maximum heart rate (HR) on a bicycle ergometer. Average power (watts/kg) within this HR range served as a previously validated proxy for CRF. Brain magnetic resonance imaging (MRI) structural analysis was done using FreeSurfer. Analyses controlled for age and sex.

Results: CRF was significantly lower in BD vs HC (0.91 ± 0.32 vs 1.01 ± 0.30, p = 0.03, F = 4.66, df=1, η =0.04). Within BD, greater depression symptoms were associated with lower CRF (P = .02), and greater physical activity (PA) was associated with greater CRF (P < .001). In multivariable analyses, there were significant main effects of diagnosis (HC>BD; P = .03) and sex (M > F; P < .001) on power. Significant predictors of power within BD included male sex (P = .02) and PA (P = .002) but not depression symptoms (P = .29). Significant diagnosis by CRF interaction effects was found in frontal, parietal, and occipital cortical regions.

Conclusion: CRF was reduced among adolescents with BD, particularly women, related in part to depression symptoms and inactivity and was differentially associated with regional brain structure. Studies seeking to improve CRF as a means of reducing psychiatric symptoms of BD are warranted.
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http://dx.doi.org/10.1111/bdi.12993DOI Listing
May 2021

Neurostructural phenotypes of CACNA1C rs1006737 in adolescents with bipolar disorder and healthy controls.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 13;104:110071. Epub 2020 Aug 13.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Pharmacology, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada. Electronic address:

Objective: Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents.

Methods: Seventy-one adolescents (14-20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume.

Results: Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions.

Conclusions: The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110071DOI Listing
January 2021

Prevalence of white matter hyperintensities is not elevated in a large sample of adolescents and young adults with bipolar disorder.

Braz J Psychiatry 2021 Mar-Apr;43(2):147-152

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Objective: The increased prevalence rate of white matter hyperintensities is one of the most consistently reported brain abnormalities in adults with bipolar disorder. However, findings in children and adolescents with bipolar disorder are less consistent. Prior studies have been constrained by small sample sizes and/or poor age- and sex-matching of healthy controls. We examined this topic in the largest sample of adolescents with bipolar disorder to date.

Methods: T2-weighted 3-Tesla magnetic resonance imaging data were acquired for 83 adolescents with bipolar disorder diagnosed via the Kiddie Schedule for Affective Disorders and the Schizophrenia, Present and Lifetime version semi-structured interview and 64 age- and sex-matched healthy controls. All acquired scans were examined by neuroradiologists and the presence or absence of white matter hyperintensities was determined for each participant.

Results: The prevalence of white matter hyperintensities did not differ between adolescents with bipolar disorder (13.3%) and controls (21.9%; χ2 = 1.90; p = 0.168).

Conclusion: In contrast to the study hypothesis, the prevalence of white matter hyperintensities was not higher in adolescents with bipolar disorder than controls. The large sample size and good matching for age and sex bolster the reliability of this negative finding. Future studies are warranted to evaluate the prevalence, incidence, and predictors of white matter hyperintensities in early-onset bipolar disorder prospectively.
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http://dx.doi.org/10.1590/1516-4446-2020-0886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023160PMC
April 2021

Markedly increased prevalence of migraine headaches in adolescents with bipolar disorder.

Bipolar Disord 2021 May 16;23(3):255-262. Epub 2020 Jul 16.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Objective: There is substantial evidence of increased prevalence of migraines, and negative psychiatric correlates of migraines, in adults with bipolar disorder (BD). Given the paucity of data on this topic in youth, we investigated the prevalence and correlates of migraine in a large sample of adolescents with BD.

Method: The study included 165 adolescents with BD-I, -II, or -not otherwise specified (NOS), diagnosed via the KSADS-PL semi-structured interview, and 89 healthy controls (HCs). Non-migraine headache and migraine headache was evaluated using the validated ID-Migraine 3-item screener.

Results: Although the prevalence of non-migraine headaches did not differ between adolescents with BD (24.2%) and HCs (32.6%; P = .15), migraine was significantly more prevalent among adolescents with BD (38.2%) compared to HCs (3.4%; adjusted odds ratio 14.76, 95% confidence interval 4.39-49.57; P < .001). Within BD, migraine was associated with female sex, BD-II/-NOS subtype, less severe worst past functioning, higher past depression severity, higher self-reported affective lability, higher body mass index, and less use of lithium and second-generation antipsychotics.

Discussion: Migraine is much more prevalent among adolescents with BD compared to HCs; the magnitude of this association exceeds what has been reported in adult samples. Correlates of migraine in youth BD are similar to those found for adults, including the link with the depressive polarity of BD. Future prospective studies are warranted to evaluate temporal associations between migraine and mood symptoms, and to evaluate neurobiological and cardiovascular underpinnings of these associations.
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http://dx.doi.org/10.1111/bdi.12972DOI Listing
May 2021

Clinical correlates of socioeconomic status in adolescent bipolar disorder.

Compr Psychiatry 2020 08 28;101:152186. Epub 2020 May 28.

Centre for Youth Bipolar Disorder, Department of Psychiatry, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Psychiatry, University of Toronto, 250 College Street, 8th floor, Toronto, ON M5T 1R8, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Rm 4207 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address:

Background: Lower socioeconomic status (SES) is associated with symptomatic severity, comorbidity, and functional impairment in adults with bipolar disorder (BD). Little is known about clinical correlates of SES in adolescents with BD.

Methods: Participants included 195 adolescents, 13-20 years old, with BD type I, II or not otherwise specified (NOS). Diagnoses were determined by standardized semi-structured interviews. Based on the Hollingshead scale, participants were divided into "low" (SES 1-3) and the "high" (SES 4-5) SES groups. Demographic and clinical correlates of SES were evaluated in univariate analyses; significant variables were evaluated in a logistic regression model.

Results: Compared to participants in the high SES group (n = 150), participants in the low SES group (n = 45) were significantly younger, less likely to be of Caucasian race and living with natural parents. In the logistic regression model, controlling for age and race, the low SES group had higher risk of police contact or arrest (OR = 2.41, 95% CI:1.14-5.11, p = 0.022), less treatment with stimulants(OR = 0.20 95% CI: 0.06-0.67, p = 0.009), and more post-traumatic stress disorder (PTSD) (OR = 4.08, 95% CI:1.33-12.46, p = 0.014) compared to the high SES group. In sensitivity analyses that further controlled for intact family, the finding of higher rates of police contact or arrest was no longer significant.

Limitations: Cross-sectional design; higher-skewed SES sample.

Conclusions: Lower SES in adolescent BD is associated with higher legal risk, increased PTSD, and under-treatment of attention-deficit/hyperactivity disorder (ADHD). Future studies are needed to evaluate the inter-relationships of these correlates, using prospective designs that can evaluate the direction of these associations. Further studies incorporating neurobiological markers are also needed to explore mechanisms underlying SES-related differences in BD.
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http://dx.doi.org/10.1016/j.comppsych.2020.152186DOI Listing
August 2020

Similarities and Differences Across Bipolar Disorder Subtypes Among Adolescents.

J Child Adolesc Psychopharmacol 2020 05 24;30(4):215-221. Epub 2020 Feb 24.

Department of Psychiatry, Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

To compare demographic, clinical, and familial characteristics across bipolar disorder (BD) subtypes in adolescents. A total of 168 participants, 13 to 19 years of age, with BD-I ( = 41), BD-II ( = 68), or operationalized BD-not otherwise specified (NOS) ( = 59) were recruited from a tertiary subspecialty clinic at an academic health sciences center. Diagnoses were determined using the semistructured K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) interview. Omnibus analyses were followed up with pairwise comparisons. After controlling for age, race, and living with both natural parents, BD-I was associated with greater functional impairment, increased rates of psychiatric hospitalization, psychosis, and lifetime exposure to second-generation antipsychotics and lithium, less self-injurious behavior, less anxiety disorders, and less severe worst lifetime depression and lower levels of emotional dysregulation and lability compared with both BD-II and BD-NOS. Lifetime most severe manic symptoms were highest in BD-I, lowest in BD-NOS, with BD-II intermediate. Lifetime exposure to psychosocial treatment followed the opposite pattern: lowest in BD-I, highest in BD-NOS, with BD-II intermediate. Variables for which there were no significant between-group differences included suicidal ideation, suicide attempts, comorbidities other than anxiety, or family history of BD. Among observed differences, most distinguish BD-I from other subtypes, whereas few variables differed between BD-II and BD-NOS. Different BD subtypes share important similarities in multiple clinical and familial characteristics, including family history of BD. Present findings support and extend knowledge regarding the course and outcome of bipolar youth study operationalized definition of BD-NOS. Further research is warranted to evaluate intermediate phenotypes and treatment strategies that address these subtype-related differences.
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http://dx.doi.org/10.1089/cap.2019.0031DOI Listing
May 2020

Preliminary study of structural magnetic resonance imaging phenotypes related to genetic variation in Interleukin-1β rs16944 in adolescents with Bipolar Disorder.

J Psychiatr Res 2020 03 31;122:33-41. Epub 2019 Dec 31.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada; Department of Pharmacology, University of Toronto, Toronto, Canada. Electronic address:

Background: Bipolar disorder (BD), among the most heritable psychiatric conditions, is associated with increased pro-inflammatory blood markers and pro-inflammatory gene expression in post-mortem brain. We therefore examined the effects of pro-inflammatory single nucleotide polymorphism interleukin-1β (IL-1β) rs16944 on brain structure in adolescents with BD and healthy control (HC) adolescents.

Methods: T-weighted 3-T magnetic resonance imaging data were acquired for 38 adolescents with BD and 32 HC adolescents (14-20 years). Using FreeSurfer, a priori regions of interest analyses, examining hippocampus, amygdala, dorsolateral prefrontal cortex (DLPFC), and caudal anterior cingulate cortex, were complemented by exploratory whole-brain vertex-wise analyses. General linear models assessed the association between IL-1β rs16944 and the ROIs, controlling for sex, age, and intracranial volume.

Results: There was an IL-1β rs16944 polymorphism-by-diagnosis interaction effect on the DLPFC; T-carriers with BD had greater surface area compared to non-carriers with BD. Whereas, HC T-carriers had smaller DLPFC volume compared to HC non-carriers. In vertex-wise analyses, similar interactions were evident in a pars triangularis surface area cluster and a lateral occipital cortex volume cluster. Whole-brain analyses also yielded a main effect of IL-1β rs16944 polymorphism, whereby T-carriers had greater lateral occipital cortex surface area and volume.

Conclusions: The IL-1β rs16944 polymorphism is associated with neurostructural phenotypes in cognitive and visual regions that subserve functions, including facial recognition and response inhibition, which are known to be aberrant in BD. Future studies are warranted to evaluate whether the observed rs16944-related structural differences are relevant to neurocognitive function, functional neuroimaging phenotypes and IL-1β protein levels.
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http://dx.doi.org/10.1016/j.jpsychires.2019.12.018DOI Listing
March 2020

Proof-of-concept study of a multi-gene risk score in adolescent bipolar disorder.

J Affect Disord 2020 02 5;262:211-222. Epub 2019 Nov 5.

Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Few studies have examined multiple genetic variants concurrently for the purpose of classifying bipolar disorder (BD); the literature among youth is particularly sparse. We selected 35 genetic variants, previously implicated in BD or associated characteristics, from which to identify the most robustly predictive group of genes.

Methods: 215 Caucasian adolescents (114 BD and 101 healthy controls (HC), ages 13-20 years) were included. Psychiatric diagnoses were determined based on semi-structured diagnostic interviews. Genomic DNA was extracted from saliva for genotyping. Two models were used to calculate a multi-gene risk score (MGRS). Model 1 used forward and backward regressions, and model 2 used a PLINK generated method.

Results: In model 1, GPX3 rs3792797 was significant in the forward regression, DRD4 exonIII was significant in the backward regression; IL1β rs16944 and DISC1 rs821577 were significant in both the forward and backward regressions. These variants are involved in dopamine neurotransmission; inflammation and oxidative stress; and neuronal development. Model 1 MGRS did not significantly discriminate between BD and HC. In model 2, ZNF804A rs1344706 was significantly associated with BD; however, this association did not predict diagnosis when entered into the weighted model.

Limitations: This study was limited by the number of genetic variants examined and the modest sample size.

Conclusions: Whereas regression approaches identified four genetic variants that significantly discriminated between BD and HC, those same variants no longer discriminated between BD and HC when computed as a MGRS. Future larger studies are needed evaluating intermediate phenotypes such as neuroimaging and blood-based biomarkers.
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http://dx.doi.org/10.1016/j.jad.2019.11.009DOI Listing
February 2020

Normal Cerebral Oxygen Consumption Despite Elevated Cerebral Blood Flow in Adolescents With Bipolar Disorder: Putative Neuroimaging Evidence of Anomalous Energy Metabolism.

Front Psychiatry 2019 11;10:739. Epub 2019 Oct 11.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Regional cerebral blood flow (CBF) is reportedly altered in both adolescents and adults with bipolar disorder (BD). Whether these CBF differences are part of an overall imbalance in cerebral energy homeostasis remains unknown. Therefore, we examined global cerebral metabolic rate of oxygen consumption (CMRO) as a physiological index of brain metabolism in adolescents with and without BD. One hundred and fifteen adolescents (mean age 17.3 ± 1.4 years), including 58 BD (type I, II, or not otherwise specified [NOS]) and 57 age-matched healthy controls (HCs) participated in this magnetic resonance imaging (MRI) study. Global estimates for venous blood oxygenation (Y) and grey matter CBF were measured using T2-relaxation-under-spin-tagging (TRUST) and arterial spin labeling (ASL) MRI, respectively. CMRO was calculated using the Fick principle of arteriovenous difference to test for a group difference. We also examined CMRO in relation to mood states (i.e. euthymic, depressed, or hypomanic/mixed). Although CBF was significantly higher in BD compared to HCs, there was no group difference in global CMRO, nor Y. Meanwhile, Y significantly decreased with age, and females tended to have greater CBF and CMRO in comparison to males. Lastly, there was no significant association between CMRO and mood states. Our results indicate a potential mismatch between cerebral blood supply and oxygen metabolism in BD, suggesting inefficiency in energy homeostasis in the brain. Mapping CMRO would provide the spatial resolution to investigate regional alterations in metabolism, particularly in the brain regions where CBF is increased.
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http://dx.doi.org/10.3389/fpsyt.2019.00739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798187PMC
October 2019

Elevated Familial Cardiovascular Burden Among Adolescents With Familial Bipolar Disorder.

Front Psychiatry 2019 29;10. Epub 2019 Jan 29.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Bipolar disorder (BD) is one of the most heritable medical conditions, and certain phenotypic characteristics are especially familial in BD. BD is also strongly associated with elevated and premature cardiovascular disease (CVD) morbidity and mortality. Thus, far, little is known regarding the familiality of cardiovascular risk in BD. We therefore examined the extent of CVD-related conditions among relatives of: adolescents with BD with a family history of BD (familial BD), adolescents with BD without a family history of BD (non-familial BD) and healthy controls (HC). The sample included 372 adolescents; 75 with familial BD, 96 with non-familial BD, and 201 HC. Parents of the adolescents completed the CARDIA Family Medical History interview regarding the adolescents' first- and second- degree adult relatives. We computed a "cardiovascular risk score" (CRS) for each relative, based on the sum of the presence of diabetes, hypertension, obesity, dyslipidemia, stroke, angina, and myocardial infarction (range 0-7). Primary analyses examined for group differences in mean overall CRS scores among first and second- degree relatives combined, controlling for age, sex, and race. Secondary analyses examined first- and second-degree relatives separately, controlling for age, sex, and race. There were significant between-group differences in CRS in first- and second- degree relatives combined, following the hypothesized ordering: CRS was highest among adolescents with familial BD (1.14 ± 0.78), intermediate among adolescents with non-familial BD (0.92 ± 0.79) and lowest in HC (0.76 ± 0.79; = 6.23, = 2, = 0.002, η = 0.03). There was a significant pairwise difference between adolescents with familial BD and HC ( = 0.002, Cohen's = 0.49). A similar pattern of between-group differences was identified when first-degree and second-degree relatives were examined separately. familial cardiovascular burden was determined based on parent interview, not evaluated directly. Adolescents with BD with a family history of BD have elevated rates of CVD-related conditions among their relatives. This may be related to genetic overlap between BD and CVD-related conditions, shared environmental factors that contribute to both BD and CVD-related conditions, or a combination of these factors. More research is warranted to better understand the interaction between familial risk for BD and CVD, and to address this risk using family-wide preventive approaches.
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http://dx.doi.org/10.3389/fpsyt.2019.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361809PMC
January 2019

Cortical Volume and Thickness Across Bipolar Disorder Subtypes in Adolescents: A Preliminary Study.

J Child Adolesc Psychopharmacol 2019 03 25;29(2):141-151. Epub 2018 Oct 25.

1 Centre for Youth Bipolar Disorder , Sunnybrook Health Sciences Centre, Toronto, Canada .

Objectives: Neuroimaging studies of adults with bipolar disorder (BD) have identified several BD subtype distinctions, including greater deficits in prefrontal gray matter volumes in BD-I (bipolar I disorder) compared to BD-II (bipolar II disorder). We sought to investigate BD subtype differences in brain structure among adolescents and young adults.

Methods: Forty-four youth with BD (14 BD-I, 16 BD-II, and 14 BD-not otherwise specified [NOS], mean age 17) underwent 3T-MRI and images were analyzed using FreeSurfer software. Cortical volume and thickness were analyzed for region of interest (ROI): ventrolateral prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate cortex (ACC), subgenual cingulate cortex, and amygdala, controlling for age, sex, and total intracranial volume. ROIs were selected as found to be implicated in BD in prior studies. A whole brain vertex-wise exploratory analysis was also performed. Uncorrected results are presented.

Results: There were group differences in ACC thickness (F = 3.88, p = 0.03, η = 0.173 uncorrected), which was reduced in BD-II in comparison to BD-I (p = 0.027 uncorrected) and BD-NOS (p = 0.019 uncorrected). These results did not survive correction for multiple comparisons and no other group differences were observed. The exploratory vertex-wise analysis found a similar pattern of lower cortical thickness in BD-II in the left and right superior frontal gyrus and left caudal middle frontal gyrus.

Conclusions: This study found reduced cortical thickness for youth with BD-II, relative to BD-I, in regions associated with cognitive control. Further neurostructural differences between subtypes may emerge later during the course of illness.
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http://dx.doi.org/10.1089/cap.2017.0137DOI Listing
March 2019

The role of self-compassion during difficult economic times.

Anxiety Stress Coping 2018 11 23;31(6):611-625. Epub 2018 Sep 23.

a Department of Psychology , York University , Toronto , Canada.

Background And Objectives: The negative effects of the financial crisis of 2007/2008 are still being felt today as seen in the relatively high levels of youth unemployment in many countries. As a result, many young people experience high stress levels when facing an uncertain and precarious job market.

Methods: Participants were 178 undergraduate students (79% female; M = 20.00, SD = 4.29) who were randomly assigned to read a news article that documented an uncertain financial future with limited job opportunities (the economic stress group), or an article that documented a tour of the Royal Canadian Mint (the control group). The role of self-compassion was explored in its relation to distress.

Results: Correlational and hierarchical regression analyses indicated that, in the economic stress group, self-compassion negatively predicted anxiety above and beyond self-esteem and familial support. In the control group, however, self-compassion did not negatively predict anxiety above and beyond self-esteem and familial support. Additionally, structural equation modeling indicated that self-compassion was directly associated with lower anxiety and indirectly related to anxiety through perceptions of financial threat.

Conclusions: These findings suggest that self-compassion may be an important resource that is associated with less distress during times of economic threat.
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http://dx.doi.org/10.1080/10615806.2018.1519703DOI Listing
November 2018

Sex differences in brain structure among adolescents with bipolar disorder.

Bipolar Disord 2018 Jun 28. Epub 2018 Jun 28.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

Objectives: Bipolar disorder (BD) is twice as prevalent amongst female as amongst male adolescents. Thus far, little is known regarding the neurostructural substrates underlying this disparity. We therefore examined sex differences in neurostructural magnetic resonane imaging (MRI) phenotypes amongst adolescents with BD.

Methods: T1-weighted structural MRI was acquired from 44 BD (25 female [F] and 19 male [M]) and 58 (28 F and 30 M) healthy control (HC) adolescents (13-21 years old). Whole-brain and region-of-interest (ROI) analyses examined structural volume and cortical thickness using FreeSurfer. ROIs included the ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), amygdala and hippocampus. General linear models evaluated sex-by-diagnosis interactions, controlling for age and intracranial volume.

Results: Whole-brain analysis revealed sex-by-diagnosis interactions in the left supramarginal gyrus (SMG) (P = .02, η  = 0.02) and right inferior parietal lobule (IPL) volumes (P = .04, η  = 0.01). Sex differences in HCs were found in the SMG (M > F) and IPL (F > M). In BD, sex differences were reversed and of smaller magnitude in the SMG (M < F) and of greater magnitude in the IPL (F > M), driven by trends towards smaller SMG and IPL in BD vs HC male participants (P = .05 and .14). Whole-brain analyses for cortical thickness, and ROI analyses for volume and cortical thickness, were not significant.

Conclusions: Normative sex differences may be disrupted in adolescent BD in the SMG and IPL, heteromodal association network hubs responsible for higher order integration of cognitive and emotional processing. Unexpectedly, these findings may inform our understanding of aberrant brain structure in adolescent BD male patients, rather than female patients. Future work should focus on replication, as well as the impact of puberty status and sex hormones on measures of brain structure and function.
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http://dx.doi.org/10.1111/bdi.12663DOI Listing
June 2018

Sex differences in brain structure among adolescents with bipolar disorder.

Bipolar Disord 2018 Jun 28. Epub 2018 Jun 28.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

Objectives: Bipolar disorder (BD) is twice as prevalent amongst female as amongst male adolescents. Thus far, little is known regarding the neurostructural substrates underlying this disparity. We therefore examined sex differences in neurostructural magnetic resonane imaging (MRI) phenotypes amongst adolescents with BD.

Methods: T1-weighted structural MRI was acquired from 44 BD (25 female [F] and 19 male [M]) and 58 (28 F and 30 M) healthy control (HC) adolescents (13-21 years old). Whole-brain and region-of-interest (ROI) analyses examined structural volume and cortical thickness using FreeSurfer. ROIs included the ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), amygdala and hippocampus. General linear models evaluated sex-by-diagnosis interactions, controlling for age and intracranial volume.

Results: Whole-brain analysis revealed sex-by-diagnosis interactions in the left supramarginal gyrus (SMG) (P = .02, η  = 0.02) and right inferior parietal lobule (IPL) volumes (P = .04, η  = 0.01). Sex differences in HCs were found in the SMG (M > F) and IPL (F > M). In BD, sex differences were reversed and of smaller magnitude in the SMG (M < F) and of greater magnitude in the IPL (F > M), driven by trends towards smaller SMG and IPL in BD vs HC male participants (P = .05 and .14). Whole-brain analyses for cortical thickness, and ROI analyses for volume and cortical thickness, were not significant.

Conclusions: Normative sex differences may be disrupted in adolescent BD in the SMG and IPL, heteromodal association network hubs responsible for higher order integration of cognitive and emotional processing. Unexpectedly, these findings may inform our understanding of aberrant brain structure in adolescent BD male patients, rather than female patients. Future work should focus on replication, as well as the impact of puberty status and sex hormones on measures of brain structure and function.
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http://dx.doi.org/10.1111/bdi.12663DOI Listing
June 2018

Retinal photography: A window into the cardiovascular-brain link in adolescent bipolar disorder.

J Affect Disord 2017 08 29;218:227-237. Epub 2017 Apr 29.

Sunnybrook Health Sciences Centre, Centre for Youth Bipolar Disorder, Toronto, Canada; University of Toronto, Department of Pharmacology and Toxicology, Toronto, Canada; Univeristy of Toronto, Department of Neurology, Toronto, Canada. Electronic address:

Objective: The burden of cardiovascular disease in bipolar disorder (BD) exceeds what can be explained by traditional cardiovascular risk factors (CVRFs), lifestyle, and/or medications. Moreover, neurocognitive deficits are a core feature of BD, and are also related to CVRFs. We examined retinal vascular photography, a proxy for cerebral microvasculature, in relation to CVRFs, peripheral microvascular function, and neurocognition among BD adolescents.

Methods: Subjects were 30 adolescents with BD and 32 healthy controls (HC). Retinal photography was conducted using a Topcon TRC 50 DX, Type IA camera, following pupil dilation. Retinal arteriolar and venular caliber was measured, from which the arterio-venular ratio (AVR) was computed. All measures were conducted masked to participant diagnosis. Peripheral arterial tonometry measured endothelial function. Neurocognition was assessed using the Cambridge Neuropsychological Tests Automated Battery.

Results: AVR was not significantly different between groups (Cohen's d=0.18, p=0.103). Higher diastolic blood pressure (BP) was associated with lower (worse) AVR in BD (r=-0.441, p=0.015) but not HC (r=-0.192, p=0.293). Similarly, in the BD group only, higher (better) endothelial function was associated with higher AVR (r=0.375, p=0.041). Hierarchical regression models confirmed that, independent of covariates, retinal vascular caliber was significantly associated with diastolic BP and endothelial function in BD. Within the BD group, mood scores were significantly negatively correlated with AVR (β=-0.451, p=0.044).

Limitations: This study's limitations include a small sample size, a cross-sectional study design, and a heterogeneous sample.

Conclusion: Retinal photography may offer unique insights regarding the cardiovascular and neurocognitive burden of BD. Larger longitudinal studies are warranted.
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http://dx.doi.org/10.1016/j.jad.2017.04.066DOI Listing
August 2017

Eight years later: outcomes of CBT-treated versus untreated anxious children.

Brain Behav 2014 Sep 19;4(5):765-74. Epub 2014 Aug 19.

University of Toronto Toronto, ON, Canada ; Department of Psychiatry, The Hospital for Sick Children Toronto, ON, Canada.

Background: Anxiety disorders are the most common psychiatric disorders of childhood, generate significant distress, are considered precursors to diverse psychiatric disorders, and lead to poor social and employment outcomes in adulthood. Although childhood anxiety has a significant impact on a child's developmental trajectory, only a handful of studies examined the long-term impact of treatment and none included a control group. The aim of this study was to conduct a long-term follow-up (LTFU) of anxious children who were treated with Cognitive-Behavioral Therapy (CBT) compared to a matched group of children who were not.

Methods: Subjects comprised 120 children: a treatment group which included the first 60 consecutive consenting children who were diagnosed with an anxiety disorder and treated with CBT between the years 1997 and 2003 and a control group, 60 matched children who were assessed but not treated with CBT. An "ex-post-facto" design was used to compare the two groups.

Results: Children showed lower rates of anxiety diagnosis (about 50% for both groups) and significantly improved functioning at LTFU (time effect P < 0.0001; no group difference). Anxiety levels were significantly lower in the nontreatment group at LTFU as compared to initial assessment (P = 0.02), but not in the treatment group, and a significant between-group difference was found (P = 0.01) according to child. An inverse relationship was found between self-efficacy/self-esteem and anxiety outcome ([P = 0.0008] and [P = 0.04], respectively).

Conclusions: This study supports the assumption that childhood anxiety disorders may improve without treatment and highlights self-efficacy/self-esteem as potential factors in recovery.
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http://dx.doi.org/10.1002/brb3.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188368PMC
September 2014

Effect of non-normality on test statistics for one-way independent groups designs.

Br J Math Stat Psychol 2012 Feb 22;65(1):56-73. Epub 2011 Mar 22.

Department of Psychology, York University, Toronto, Canada.

The data obtained from one-way independent groups designs is typically non-normal in form and rarely equally variable across treatment populations (i.e., population variances are heterogeneous). Consequently, the classical test statistic that is used to assess statistical significance (i.e., the analysis of variance F test) typically provides invalid results (e.g., too many Type I errors, reduced power). For this reason, there has been considerable interest in finding a test statistic that is appropriate under conditions of non-normality and variance heterogeneity. Previously recommended procedures for analysing such data include the James test, the Welch test applied either to the usual least squares estimators of central tendency and variability, or the Welch test with robust estimators (i.e., trimmed means and Winsorized variances). A new statistic proposed by Krishnamoorthy, Lu, and Mathew, intended to deal with heterogeneous variances, though not non-normality, uses a parametric bootstrap procedure. In their investigation of the parametric bootstrap test, the authors examined its operating characteristics under limited conditions and did not compare it to the Welch test based on robust estimators. Thus, we investigated how the parametric bootstrap procedure and a modified parametric bootstrap procedure based on trimmed means perform relative to previously recommended procedures when data are non-normal and heterogeneous. The results indicated that the tests based on trimmed means offer the best Type I error control and power when variances are unequal and at least some of the distribution shapes are non-normal.
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http://dx.doi.org/10.1111/j.2044-8317.2011.02014.xDOI Listing
February 2012

Narrative skills in children with selective mutism: an exploratory study.

Am J Speech Lang Pathol 2004 Nov;13(4):304-15

The Hospital for Sick Children, Toronto, Ontario, Canada.

Selective mutism (SM) is a rare and complex disorder associated with anxiety symptoms and speech-language deficits; however, the nature of these language deficits has not been studied systematically. A novel cross-disciplinary assessment protocol was used to assess anxiety and nonverbal cognitive, receptive language, and expressive narrative abilities in 7 children with SM and a comparison group of 7 children with social phobia (SP). The children with SM produced significantly shorter narratives than children with SP, despite showing normal nonverbal cognitive and receptive language abilities. The findings suggest that SM may involve subtle expressive language deficits that may influence academic performance and raise additional questions for further research. The assessment procedure developed for this study may be potentially useful for language clinicians.
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http://dx.doi.org/10.1044/1058-0360(2004/031)DOI Listing
November 2004

Characterizing selective mutism: is it more than social anxiety?

Depress Anxiety 2003 ;18(3):153-61

Department of Psychiatry, Hospital for Sick Children, Toronto, Ontario, Canada.

Selective mutism (SM) occurs when a child persistently lacks speech in some social situations but not in others, despite the ability to use and comprehend language. While considered to be related to anxiety, SM is poorly understood and studies of SM children are often based on parent reports. This study developed a unique, non-verbally based assessment protocol for SM children in order to better characterize their clinical profile, language abilities, and learning abilities. A comparison was done with a group of children of similar age, with social phobia (SP) but no SM, to search for characteristics that might distinguish SM from other anxiety disorders. Twenty-three children participated in the study (14 SM and 9 SP). The assessment protocol included standardized anxiety rating scales, cognitive and academic tests, and a speech and language assessment. SM and SP groups showed similar levels of anxiety and academic ability, but the SM group showed some language impairments relative to the SP group. Though requiring replication with a larger sample and nonclinical comparison group, the results suggest that SM children can be assessed by non-verbal means and that their disorder is characterized by anxiety and subtle language impairments.
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http://dx.doi.org/10.1002/da.10125DOI Listing
March 2004

Group and individual cognitive-behavioral therapy for childhood anxiety disorders: a randomized trial.

J Am Acad Child Adolesc Psychiatry 2002 Dec;41(12):1423-30

Department of Psychiatry, Hospital for Sick Children, Toronto, Canada.

Objective: To compare the efficacy of group and individual cognitive-behavioral therapy (CBT) in children with Axis I anxiety disorders. It was hypothesized that certain subgroups would respond preferentially to one modality.

Method: Seventy-eight children aged 8-12 years with diagnosed anxiety disorders were randomly assigned to a 12-week, manual-based program of group or individual CBT, both with parental involvement. Outcomes included child anxiety (child and parent report) and global functioning as estimated by clinicians. Repeated-measures analyses of variance (ANOVAs) were done. The sample was then dichotomized by self-reported social anxiety (high/low) and parent-reported hyperactivity (high/low) using median splits, and diagnostically by generalized anxiety disorder versus phobic disorders. ANOVAs were repeated.

Results: Children and parents reported significantly decreased anxiety and clinicians reported significantly improved global functioning regardless of treatment modality. Children reporting high social anxiety reported greater gains in individual treatment than in group treatment (p <.01). Parent reports of hyperactivity and diagnostic differences were not associated with differential treatment response by modality.

Conclusions: Children with anxiety disorders appear to improve with CBT, whether administered in a group or individual format. A subgroup of children reporting high social anxiety may respond preferentially to individual treatment. Replication of these findings is indicated.
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http://dx.doi.org/10.1097/00004583-200212000-00013DOI Listing
December 2002

Web-based CBT for selective mutism.

J Am Acad Child Adolesc Psychiatry 2002 Feb;41(2):112-3

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http://dx.doi.org/10.1097/00004583-200202000-00003DOI Listing
February 2002