Dataset Information

Lithium Versus Other Mood-Stabilizing Medications in a Longitudinal Study of Youth Diagnosed With Bipolar Disorder.

ABSTRACT:

Objective

Lithium is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youths is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether lithium vs other mood-stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality.

Method

COBY is a naturalistic, longitudinal study of 413 youths, 7 to 17.11 years old at intake, with BD. At each visit, medication exposure, psychiatric symptoms, and psychosocial function over the preceding follow-up period were assessed using the Adolescent Longitudinal Interval Follow-Up Evaluation. Using mixed models, we determined whether participants taking lithium vs OMS (but not lithium) differed regarding mood symptoms, suicidality, psychosocial function, hospitalization, aggression, and substance use.

Results

A total of 340 participants contributed 2,638 six-month follow-up periods (886 lithium, 1,752 OMS), over a mean follow-up of 10 years. During lithium (vs OMS) follow-up periods, participants were older, less likely to have lifetime anxiety, and less likely to be on antidepressants (p values<.005). After covariate adjustment, the lithium group (vs OMS) had half as many suicide attempts (p = .03), fewer depressive symptoms (p = .004), less psychosocial impairment (p = .003), and less aggression (p = .0004). Similar findings were observed in the subgroup of follow-up periods in which participants were <18 years old.

Conclusion

Findings are consistent with adult studies, showing that lithium is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youths with BD.

SUBMITTER: Hafeman DM

PROVIDER: S-EPMC6987013 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Lithium Versus Other Mood-Stabilizing Medications in a Longitudinal Study of Youth Diagnosed With Bipolar Disorder.

Hafeman Danella M DM Rooks Brian B Merranko John J Liao Fangzi F Gill Mary Kay MK Goldstein Tina R TR Diler Rasim R Ryan Neal N Goldstein Benjamin I BI Axelson David A DA Strober Michael M Keller Martin M Hunt Jeffrey J Hower Heather H Weinstock Lauren M LM Yen Shirley S Birmaher Boris B

Journal of the American Academy of Child and Adolescent Psychiatry 20190729 10

<h4>Objective</h4>Lithium is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youths is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether lithium vs other mood-stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality.<h4>Method</h4>COBY is a naturalistic, longitudinal study of 413 youths, 7 to 17.11 years old at intake, with BD. At each visit, medication exposure, psychia ...[more]

PMID: 31369795

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Project description:BackgroundClinical neuroimaging studies often investigate group differences between patients and controls, yet multivariate imaging features may enable individual-level classification. This study aims to classify youth with bipolar disorder (BD) versus healthy youth using grey matter cerebral blood flow (CBF) data analyzed with logistic regressions.MethodsUsing a 3 Tesla magnetic resonance imaging (MRI) system, we collected pseudo-continuous, arterial spin-labelling, resting-state functional MRI (rfMRI) and T 1-weighted images from youth with BD and healthy controls. We used 3 logistic regression models to classify youth with BD versus controls, controlling for age and sex, using mean grey matter CBF as a single explanatory variable, quantitative CBF features based on principal component analysis (PCA) or relative (intensity-normalized) CBF features based on PCA. We also carried out a comparison analysis using rfMRI data.ResultsThe study included 46 patients with BD (mean age 17 yr, standard deviation [SD] 1 yr; 25 females) and 49 healthy controls (mean age 16 yr, SD 2 yr; 24 females). Global mean CBF and multivariate quantitative CBF offered similar classification performance that was above chance. The association between CBF images and the feature map was not significantly different between groups (p = 0.13); however, the multivariate classifier identified regions with lower CBF among patients with BD (ΔCBF = -2.94 mL/100 g/min; permutation test p = 0047). Classification performance decreased when considering rfMRI data.LimitationsWe cannot comment on which CBF principal component is most relevant to the classification. Participants may have had various mood states, comorbidities, demographics and medication records.ConclusionBrain CBF features can classify youth with BD versus healthy controls with above-chance accuracy using logistic regression. A global CBF feature may offer similar classification performance to distinct multivariate CBF features.

Project description:This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients.

Project description:ObjectiveEpidemiological studies suggest that patients with attention-deficit/hyperactivity disorder (ADHD) treated with amphetamines have an increased risk of newly diagnosed psychosis. This risk in youth is poorly understood. This investigation studied the potential risk of newly diagnosed psychotic symptoms associated with exposure to 4 classes of ADHD medications.MethodThis retrospective study used a medical records-linkage system from a cohort of youth (age 6-18 years) with diagnosed ADHD who were prescribed amphetamines, methylphenidate, atomoxetine, or α-2 agonists. Cohort members with any diagnosis of psychosis before their first ADHD medication were excluded. The primary outcome was newly diagnosed psychotic symptoms. The risk for psychotic symptoms for each medication (vs the remaining medication classes combined) was estimated using a multivariable time-varying covariate Cox proportional hazard regression model that adjusted for sex and age at ADHD diagnosis.ResultsOf 5,171 youth (68.6% male), 134 (2.6 %) had newly diagnosed psychotic symptoms. Exposure to amphetamine (vs amphetamine nonexposure, hazard ratio 1.41, 95% CI 1.15-2.26) and atomoxetine (vs atomoxetine nonexposure, hazard ratio 2.01, 95% CI 1.38-2.92) was associated with increased risk of newly diagnosed psychotic symptoms. Secondary analysis showed that the frequency of newly diagnosed psychotic symptoms was higher with atomoxetine/stimulant lifetime combination therapy (12.5% with amphetamines, 7.7% with methylphenidate) than atomoxetine monotherapy (1.2%).ConclusionRisk of newly diagnosed psychotic symptoms was low. These results suggest that cumulative exposure to amphetamines or atomoxetine/stimulant lifetime combination therapy may be associated with an increased risk of newly diagnosed psychotic symptoms in youth with ADHD.Diversity & inclusion statementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Project description:CONTEXT Youth with bipolar disorder (BD) and those with severe, nonepisodic irritability (severe mood dysregulation [SMD]) exhibit amygdala dysfunction during facial emotion processing. However, studies have not compared such patients with each other and with comparison individuals in neural responsiveness to subtle changes in facial emotion; the ability to process such changes is important for social cognition. To evaluate this, we used a novel, parametrically designed faces paradigm. OBJECTIVE To compare activation in the amygdala and across the brain in BD patients, SMD patients, and healthy volunteers (HVs). DESIGN Case-control study. SETTING Government research institute. PARTICIPANTS Fifty-seven youths (19 BD, 15 SMD, and 23 HVs). MAIN OUTCOME MEASURE Blood oxygenation level-dependent data. Neutral faces were morphed with angry and happy faces in 25% intervals; static facial stimuli appeared for 3000 milliseconds. Participants performed hostility or nonemotional facial feature (ie, nose width) ratings. The slope of blood oxygenation level-dependent activity was calculated across neutral-to-angry and neutral-to-happy facial stimuli. RESULTS In HVs, but not BD or SMD participants, there was a positive association between left amygdala activity and anger on the face. In the neutral-to-happy whole-brain analysis, BD and SMD participants modulated parietal, temporal, and medial-frontal areas differently from each other and from that in HVs; with increasing facial happiness, SMD patients demonstrated increased, and BD patients decreased, activity in the parietal, temporal, and frontal regions. CONCLUSIONS Youth with BD or SMD differ from HVs in modulation of amygdala activity in response to small changes in facial anger displays. In contrast, individuals with BD or SMD show distinct perturbations in regions mediating attention and face processing in association with changes in the emotional intensity of facial happiness displays. These findings demonstrate similarities and differences in the neural correlates of facial emotion processing in BD and SMD, suggesting that these distinct clinical presentations may reflect differing dysfunctions along a mood disorders spectrum.

Dataset Information

Lithium Versus Other Mood-Stabilizing Medications in a Longitudinal Study of Youth Diagnosed With Bipolar Disorder.

Objective

Method

Results

Conclusion

Publications

Lithium Versus Other Mood-Stabilizing Medications in a Longitudinal Study of Youth Diagnosed With Bipolar Disorder.

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