Victoria E. Cosgrove

Early Intervention for Symptomatic Youth at Risk for Bipolar Disorder: A Randomized Trial of Family- Focused Therapy

OBJECTIVE Depression and brief periods of (hypo)mania are linked to an increased risk of progression to bipolar I or II disorder (BD) in children of bipolar parents. This randomized trial examined the effects of a 4-month family-focused therapy (FFT) program on the 1-year course of mood symptoms in youth at high familial risk for BD, and explored its comparative benefits among youth in families with high versus low expressed emotion (EE). METHOD Participants were 40 youth (mean 12.3±2.8 years, range 9-17) with BD not otherwise specified, major depressive disorder, or cyclothymic disorder who had a first-degree relative with BD I or II and active mood symptoms (Young Mania Rating Scale [YMRS]>11 or Child Depression Rating Scale>29). Participants were randomly allocated to FFT-High Risk version (FFT-HR; 12 sessions of psychoeducation and training in communication and problem-solving skills) or an education control (EC; 1-2 family sessions). RESULTS Youth in FFT-HR had more rapid recovery from their initial mood symptoms (hazard ratio = 2.69, p = .047), more weeks in remission, and a more favorable trajectory of YMRS scores over 1 year than youth in EC. The magnitude of treatment effect was greater among youth in high-EE (versus low-EE) families. CONCLUSIONS FFT-HR may hasten and help sustain recovery from mood symptoms among youth at high risk for BD. Longer follow-up will be necessary to determine whether early family intervention has downstream effects that contribute to the delay or prevention of full manic episodes in vulnerable youth.

Structure and etiology of co-occurring internalizing and externalizing disorders in adolescents.

Several studies suggest that a two-factor model positing internalizing and externalizing factors explains the interrelationships among psychiatric disorders. However, it is unclear whether the covariation between internalizing and externalizing disorders is due to common genetic or environmental influences. We examined whether a model positing two latent factors, internalizing and externalizing, explained the interrelationships among six psychiatric disorders (major depressive disorder, generalized anxiety disorder, separation anxiety disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder) in adolescents, and whether there are common genetic and environmental influences on internalizing and externalizing latent factors. Multivariate behavior genetic analyses of data from 1162 twin pairs and 426 siblings ascertained from the general population via the Colorado Center for Antisocial Drug Dependence (CADD) were conducted. We found support for a model positing two latent factors (internalizing and externalizing). These factors were moderately heritable and influenced by significant common genetic and nonshared environmental influences. These findings suggest that co-occurrence of internalizing and externalizing psychopathology in adolescents results from both genetic and environmental influences.

Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia

BackgroundThe fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate.DiscussionFamily studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research.SummaryFor DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis.

Toward a Valid Animal Model of Bipolar Disorder: How the Research Domain Criteria Help Bridge the Clinical-Basic Science Divide

Bipolar disorder is a diagnostically heterogeneous disorder, although mania emerges as a distinct phenotype characterized by elevated mood and increased activity or energy. While bipolar disorders cyclicity is difficult to represent in animals, models of mania have begun to decode its fundamental underlying neurobiology. When psychostimulants such as amphetamine or cocaine are administered to rodents, a resulting upsurge of motor activity is thought to share face and predictive validity with mania in humans. Studying black Swiss mice, which inherently exhibit proclivity for reward seeking and risk taking, also has yielded some insight. Further, translating the biology of bipolar disorder in humans into animal models has led to greater understanding of roles for candidate biological systems such as the GRIK2 and CLOCK genes, as well as the extracellular signal-related kinase pathway involved in the pathophysiology of the illness. The National Institute of Mental Health Research Domain Criteria initiative seeks to identify building blocks of complex illnesses like bipolar disorder in hopes of uncovering the neurobiology of each, as well as how each fits together to produce syndromes like bipolar disorder or why so many mental illnesses co-occur together. Research Domain Criteria-driven preclinical models of isolated behaviors and domains involved in mania and bipolar disorder will ultimately inform movement toward nosology supported by neurobiology.

Bipolar Depression in Pediatric Populations

Depression in children and adolescents with bipolar disorder is more commonly observed than mania or hypomania, and is associated with significant functional disability in multiple environmental realms. Optimal management of pediatric bipolar depression is often defined by its multimodal nature with emphasis on both psychopharmacological and psychosocial treatment. This article provides a brief overview of the epidemiology and clinical course of pediatric bipolar depression, a clinically-oriented guide to the evidence-based psychopharmacological and psychosocial management of bipolar depression in youth, and suggestions on how best to integrate medication and therapy. Recommended treatment for bipolar depression in pediatric populations usually includes both medication and psychosocial interventions given a paucity of double-blind, placebo-controlled psychopharmacological studies. Lithium and lamotrigine are feasible and tentatively efficacious options; however, treatment with quetiapine monotherapy may be no better than placebo. Furthermore, some youth may be at heightened risk for developing manic symptoms after treatment with selective serotonin reuptake inhibitors (SSRIs). Psychotherapy, either alone or adjunctively with medications, provides practitioners with a safe and feasible alternative. Interpersonal and Social Rhythm Therapy for Adolescents (IPSRT-A), Child- and Family-Focused Cognitive Behavioral Therapy (CFF-CBT), Dialectical Behavior Therapy for Adolescents (DBT-A), family psychoeducation, and Family Focused Therapy for Adolescents (FFT-A) are evidence-based treatments available to clinicians treating youth with bipolar depression.

First controlled treatment trial of bipolar II hypomania with mixed symptoms: Quetiapine versus placebo

OBJECTIVES To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Family support and depressive symptoms: a 23-year follow-up†

We examined change in family support and depressive symptoms over the course of 23 years and included the potential moderators of gender and participation in treatment. A sample of 373 depressed individuals provided data in five waves, with baseline, 1-year, 4-year, 10-year, and 23-year follow-ups. Multilevel modeling was used to evaluate longitudinal relationships between variables. Higher family support was associated with less depression at baseline and predicted a steeper trajectory of recovery from depression over 23 years. This relationship was moderated by gender, such that women with supportive families reported the most rapid recovery from depression. Evaluating family context may be clinically relevant when beginning treatment with a depressed patient, particularly for female patients.

A Randomized, Double-Blind, Placebo-Controlled Study of Ziprasidone Monotherapy in Bipolar Disorder With Co-Occurring Lifetime Panic or Generalized Anxiety Disorder

OBJECTIVE Bipolar disorder often co-occurs with anxiety disorders. Evidence suggests that second-generation antipsychotics (SGAs) may be useful in treating both conditions. This study examined the efficacy of ziprasidone in the treatment of these disorders. METHOD This 3-site, randomized, double-blind, placebo-controlled, parallel group, 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder (with or without agoraphobia) or generalized anxiety disorder (GAD) experiencing moderately severe anxiety symptoms at entrance into the study. Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria. Patients were screened and randomized from June 25, 2010, through August 23, 2011. Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale (CGI-21 Anxiety) and the Sheehan Disability Scale (SDS), with secondary measures monitoring anxiety and mood symptoms. RESULTS Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety (F1 = 0.34; P = .564) or SDS (F1 = 0.26; P = .611). Secondary analysis using hierarchical linear modeling found similar results (CGI-21 Anxiety: F1 = 1.82; P = .178; and SDS: F1 = 0.70; P = .408). Regardless of group, time in the study was associated with significant decrease in anxiety (F1 = 11.08; P = .001) and total disability (F1 = 26.16; P < .001). Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement, and 81.8% (n = 9) of the subjects who withdrew from the study due to adverse events, serious adverse events, or side effects were in the ziprasidone group. CONCLUSIONS Results suggest that ziprasidone monotherapy was not associated with a clinically significant improvement in anxiety symptoms or improved function for patients with bipolar disorder, lifetime panic disorder or GAD, and concurrent moderately severe anxiety symptoms, and it was associated with a more negative side-effect profile relative to placebo. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01172652.

Online ethics: where will the interface of mental health and the internet lead us?

While e-health initiatives are poised to revolutionize delivery and access to mental health care, conducting clinical research online involves specific contextual and ethical considerations. Face-to-face psychosocial interventions can at times entail risk and have adverse psychoactive effects, something true for online mental health programs too. Risks associated with and specific to internet psychosocial interventions include potential breaches of confidentiality related to online communications (such as unencrypted email), data privacy and security, risks of self-selection and self-diagnosis as well as the shortcomings of receiving psychoeducation and treatment at distance from an impersonal website. Such ethical issues need to be recognized and proactively managed in website and study design as well as treatment implementation. In order for online interventions to succeed, risks and expectations of all involved need to be carefully considered with a focus on ethical integrity.

Association between 5HTT, DAT1, and DRD4 and bipolar disorder in youth.

Bipolar disorder (BD) in youth is characterized by rapid fluctuation between high and low mood states, severe irritability, and multiple psychiatric comorbidities. Left untreated, affected youth may demonstrate compromised development in social, neurobiological, cognitive, and emotional realms (Miklowitz & Cicchetti 2006). Given the marked genetic loading associated with pediatric BD (Leibenluft 2008), identifying genetic risk profiles may prove critical for understanding its onset. The present study examined relationships between BD in youth and the 5HTT-linked polymorphic region (5HTTLPR) in the serotonin transporter (5HTT, SLC6A4), a 40-base pair Variable Number Tandem Repeat (VNTR) polymorphism in the 3′ untranslated region of the dopamine transporter (DAT1, SLC6A3), and a 44-base pair VNTR in exon 3 of the dopamine D4 receptor (DRD4). Given possible relevance of age, we also examined interaction effects of age and genotype on symptoms of depression in youth with BD. Genomic DNA was collected from youth meeting DSM-IV criteria for BD I, II, or Not Otherwise Specified (n=62) recruited in a research clinic at the University of Colorado at Boulder and controls (n=239) from the Colorado Twin Registry. All loci were in Hardy-Weinberg equilibrium. 5HTTLPR (χ2=1.79, df=2, p=.41; cases: short/short (S/S)=8, long/long (L/L)=22, S/L=32, controls: S/S=48, L/L=78, S/L=110), DAT1 3′ UTR VNTR (χ2= 1.51, df=2, p=.47; cases: S/S=5, L/L=34, S/L=22, controls: S/S=12, L/L=124, S/L=102), and DRD4 VNTR (χ2=.05, df=2, p=.97; cases: S/S=38, L/L=3, S/L=19, controls: S/S=149, L/L=11, S/L=79) did not show significant association with DSM-IV BD. The lack of inclusion of the LA/LG 5HTTLRP SNP (Hu et al. 2005) was a limitation of the present study. Regression models including age, genotype, and their interaction significantly predicted Depression Rating Scale (DRS; Kaufman et al. 1997) scores in youth with BD for 5HTTLPR (F=3.46, df=3, p=.02) and DRD4 (F=3.76, df=3, p=.02). Effects of age (5HTTLPR: t=2.83, p=.01; DRD4: t=2.02, p=.05) and age x genotype interaction (5HTTLPR: t=2.59, p=.01; DRD4: t=2.59, p=.01) were significant; for both, DRS scores increased more steeply with progressing age as the number of L alleles increased. In summary, we found no evidence of an association between 5HTT, DAT1, and DRD4 and DSM-IV BD but evidence of a genotype x age interaction effect for 5HTT and DRD4 on a measure of depressive symptoms in youth with BD spectrum disorders. Since 5HTT, DAT1, and DRD4 have been linked with BD in adults (Escamilla & Zavala 2008), symptoms common in youth (e.g., irritability) may show weaker associations with these markers than those more frequently observed in adult BD (e.g., elevated mood, hypersexuality, grandiosity). Depression in pediatric BD may worsen in part as a function of genotype as youth get older and approach adulthood. Whereas the L variant of the DRD4 VNTR appears to react less strongly to dopamine molecules linked to the brain’s reward system, the 5HTTLPR L allele is thought to lead to greater transport of serotonin which is associated with regulation of emotions and drives. The effect of dopaminergic and serotonergic gene expression on depressive symptoms in youth may change with age.