Publications by authors named "Mikaela K Dimick"

7 Publications

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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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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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March 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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February 2021

Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and methodology.

Contemp Clin Trials Commun 2020 Sep 23;19:100600. Epub 2020 Jun 23.

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

Introduction: Depressive symptoms predominate in the course of bipolar disorder (BD) and there is an urgent need to evaluate novel application of repurposed compounds that act on pre-specified treatment targets. Several lines of reasoning suggest that nitrous oxide (NO) is an ideal medication to study as a potential treatment and as a strategy to identify the underlying pathophysiology of bipolar depression. NO is a potent cerebral vasodilator and there is compelling evidence of reduced frontal cerebral blood flow (CBF; i.e. hypoperfusion) in depression. Therefore, NO may increase CBF and thereby improve symptoms of depression. The goal of this randomized, double-blind trial is to study the effect of a single administration of NO versus the active comparator midazolam on mood and CBF in adults with treatment-resistant bipolar depression.

Methods: Participants with BD-I/-II currently experiencing a major depressive episode will be randomized to one of two conditions (n = 20/group): 1) inhaled NO plus intravenous saline, or 2) inhaled room air plus intravenous midazolam. Montgomery-Asberg Depression Rating Scale scores will serve as the primary endpoint. CBF will be measured via arterial spin labelling magnetic resonance imaging.

Conclusions: NO is a potential novel treatment for bipolar depression, as it causes cerebral vasodilation. This proof-of-concept study will provide valuable information regarding the acute impact of NO on mood and on CBF. If NO proves to be efficacious in future larger-scale trials, its ubiquity, safety, low cost, and ease of use suggest that it has great potential to become a game-changing acute treatment for bipolar depression.
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September 2020

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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August 2020

Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder.

J Psychiatr Res 2020 04 10;123:187-193. Epub 2020 Feb 10.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada. Electronic address:

Background: Mitochondrial dysfunction has been implicated in the pathophysiology of bipolar disorder (BD). Impediment of mitochondrial oxidative phosphorylation results in a shift toward anaerobic respiration and lactate production. Elevated CNS lactate levels in adults with BD inform the need to evaluate lactate in peripheral samples and early in the course of BD. Furthermore, there exists a recent surge of investigations looking at circulating cell-free mitochondrial DNA (ccf-mtDNA) as a potential biomarker as they are released from cells under physiological stress, apoptosis, or bioenergetic compromise.

Objectives: To compare lactate and ccf-mtDNA, two different ways in assessing the mitochondrial health and function, in adolescents with BD versus healthy control adolescents (HC).

Methods: One-hundred and five adolescents (n = 64 BD, n = 41 HC) were included. Serum lactate level was measured using a commercially available colorimetric kit. Serum ccf-mtDNA concentration was measured using quantitative polymerase chain reaction from ccfDNA purified by commercially available spin columns. Diagnosis and mood symptoms were evaluated using semi-structured interviews.

Results: There is an increase in serum lactate level of adolescents with BD (1.319 ± 0.444 nmol/uL) versus HC (1.168 ± 0.353 nmol/uL; p = 0.043), but not ccf-mtDNA. Among BD adolescents, depression symptoms were negatively correlated with ccf-mtDNA levels (ρ = -0.289; p = 0.038) but loses significance when corrected for multiple comparison. Lactate was positively correlated with ccf-mtDNA in the overall sample (ρ = 0.201; p = 0.043). When examined by diagnosis, this association remained in BD (ρ = 0.273; p = 0.032), but not HC.

Conclusion: These preliminary results indicate that elevated lactate is observed even among adolescents early in their course of BD, that the association between lactate and ccf-mtDNA appears to be specific to BD, and that ccf-mtDNA is potentially associated with depression symptoms in adolescent BD. In addition, the effect of psychotropic medications used in the treatment of BD on peripheral lactate and ccf-mtDNA requires further investigation.
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April 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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February 2020