Kelly Monk

Fluoxetine for the Treatment of Childhood Anxiety Disorders

OBJECTIVE To assess the efficacy and tolerability of fluoxetine for the acute treatment of children and adolescents with generalized anxiety disorder, separation anxiety disorder, and/or social phobia. METHOD Anxious youths (7-17 years old) who had significant functional impairment were randomized to fluoxetine (20 mg/day) (n = 37) or placebo (n = 37) for 12 weeks. RESULTS Fluoxetine was effective in reducing the anxiety symptoms and improving functioning in all measures. Using intent-to-treat analysis, 61% of patients taking fluoxetine and 35% taking placebo showed much to very much improvement. Despite this improvement, a substantial group of patients remained symptomatic. Fluoxetine was well tolerated except for mild and transient headaches and gastrointestinal side effects. Youths with social phobia and generalized anxiety disorder responded better to fluoxetine than placebo, but only social phobia moderated the clinical and functional response. Severity of the anxiety at intake and positive family history for anxiety predicted poorer functioning at the end of the study. CONCLUSIONS Fluoxetine is useful and well tolerated for the acute treatment of anxious youths. Investigations regarding the optimization of treatment to obtain full anxiety remission and the length of treatment necessary to prevent recurrences are warranted.

Replicable differences in preferred circadian phase between bipolar disorder patients and control individuals

Morningness/eveningness (M/E) is a stable, quantifiable measure reflecting preferred circadian phase. Two prior studies suggest that bipolar I disorder (BP1) cases are more likely to have lower M/E scores, i.e., be evening types compared with control groups. These studies did not recruit controls systematically and did not evaluate key clinical variables. We sought to replicate the reported associations in a large, well defined sample, while evaluating potential confounding factors. Adults with bipolar disorder (BP) were compared with community controls drawn randomly from the same residential areas (190 cases and 128 controls). M/E was evaluated using the composite scale of morningness (CSM). After accounting for variables correlated with M/E, BP cases had significantly lower CSM scores than controls (i.e., more evening-type or fewer morning-type). There were no significant differences in M/E scores between BP1 or BP2 disorder cases (n=134 and 56, respectively). CSM scores were stable over approximately 2 years in a subgroup of participants (n=52). Individuals prescribed anxiolytic drugs, antidepressants, antipsychotic drugs, mood stabilizers or stimulant drugs had significantly lower age-corrected CSM scores compared with persons not taking these drugs. BP cases are more likely to be evening types, suggesting circadian phase delay in BP cases. Individuals with elevated depressive mood scores are more likely to be evening types. Our results suggest a replicable relationship between circadian phase and morbid mood states.

Schedule for Affective Disorders and Schizophrenia for School- Age Children (K-SADS-PL) for the Assessment of Preschool Children- A Preliminary Psychometric Study

OBJECTIVE To assess the psychometrics of the schedule for affective disorders and schizophrenia for school-age children present and lifetime version (K-SADS-PL) in diagnosing DSM-IV psychiatric disorders and subsyndromal symptomatology in preschool children. METHOD Parents were interviewed about their children using the K-SADS-PL, and they completed the early childhood inventory-4 (ECI-4) and child behavior checklist for ages 1(1/2)-5 years (CBCL). Discriminant, divergent, and convergent validity of the K-SADS-PL were evaluated in 204 offspring ages 2-5 years old of parents from an ongoing study. Inter-rater reliability as well as predictive validity of intake diagnoses at second assessment approximately two years after intake were evaluated. Fourteen children were also assessed by the preschool age psychiatric assessment (PAPA). RESULTS Children who were diagnosed with oppositional defiant disorder, attention deficit hyperactivity disorder, anxiety, mood, or elimination disorders had significantly higher scores on the ECI-4 than children without these disorders. Significant correlations were found for all convergent CBCL scales. Divergent validity was acceptable for emotional disorders. Inter-rater kappa coefficients for all diagnoses were good. Above noted results were similar for children with at least one positive K-SADS-PL key screen symptom. A significantly higher percentage of children with an intake diagnosis had a diagnosis approximately two years after intake compared to those without an intake disorder. Overall, there was consistency between the PAPA and the K-SADS-PL. CONCLUSIONS Pending further testing, the K-SADS-PL may prove useful for the assessment of psychopathology in preschoolers.

Subcortical Gray Matter Volume Abnormalities in Healthy Bipolar Offspring: Potential Neuroanatomical Risk Marker for Bipolar Disorder?

OBJECTIVE A growing number of structural neuroimaging studies have shown that bipolar disorder (BD) is associated with gray matter (GM) volume abnormalities in brain regions known to support affect regulation. The goal of this study was to examine whole-brain regional GM volume in healthy bipolar offspring (HBO) relative to age-matched controls to identify possible structural abnormalities that may be associated with risk for BD. METHOD Participants were 20 youths (8-17 years old) with at least one parent diagnosed with BD, and 22 age-matched healthy individuals. All of them were free of Axis I diagnoses. High-resolution magnetic resonance imaging structural images were acquired using a 3-T Siemens scanner. Voxel-based morphometric analyses were conducted using SPM5. RESULTS Relative to controls, HBO had significantly increased GM volume in left parahippocampal/hippocampal gyrus (p <.05 corrected), following whole-brain analyses. This increase was correlated with puberty but not age in HBO. Region-of-interest analyses on the amygdala and orbitomedial prefrontal cortex did not yield any significant group differences after conducting small volume correction. CONCLUSIONS The pattern of increased GM volume in parahippocampal/hippocampal gyrus in HBO suggests a potential marker for risk for BD. It can also be considered as a potential neuroprotective marker for the disorder because HBO were free of current psychopathology. Prospective studies examining the relationship between changes in GM volume in these regions and subsequent development of BD in HBO will allow us to elucidate further the role of this region in either conferring risk for or protecting against the development of BD.

Is bipolar disorder specifically associated with aggression

Ballester J, Goldstein T, Goldstein B, Obreja M, Axelson D, Monk K, Hickey MB, Iyengar S, Farchione T, Kupfer DJ, Brent D, Birmaher B. Is bipolar disorder specifically associated with aggression? Bipolar Disord 2012: 14: 283–290.

Psychosocial functioning in offspring of parents with bipolar disorder

BACKGROUND Offspring of parents with bipolar disorder are at increased risk for a range of psychopathology, including bipolar disorder. It is not clear if they also have impairments in their psychosocial functioning. METHODS We compared the psychosocial functioning of three groups of children enrolled in the Pittsburgh Bipolar Offspring Study (BIOS): offspring of probands with bipolar disorder (n=388), offspring of probands with other types of psychopathology (n=132), and offspring of healthy probands (n=118). Psychosocial functioning was assessed at study intake using the schedule of the Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE), the Child Behavior Check List (CBCL) and the Childrens Global Assessment Scale (CGAS). RESULTS Offspring of probands with bipolar disorder exhibited impairments in various aspects of psychosocial functioning. On all measures, they had worse functioning in comparison with offspring of healthy probands. Offspring of probands with bipolar disorder generally exhibited more impairment than offspring of probands with nonbipolar psychopathology. After adjusting for proband parent functioning and the childs Axis I psychopathology, functioning of offspring of probands with bipolar disorder was similar to that of offspring of healthy probands. LIMITATIONS Data are cross-sectional and therefore do not allow for causal conclusions about the association between parental psychopathology, child psychopathology and offspring psychosocial functioning. CONCLUSIONS Offspring of parents with bipolar disorder exhibit impairments in psychosocial functioning which appear largely attributable to proband parent functional impairment and the childs own psychopathology. As such, interventions to improve parental functioning, as well as early interventions to treat the childs psychopathology may help reduce the risk for long-term functional impairment in offspring.

Dimensional psychopathology in offspring of parents with bipolar disorder.

Diler RS, Birmaher B, Axelson D, Obreja M, Monk K, Hickey MB, Goldstein B, Goldstein T, Sakolsky D, Iyengar S, Brent D, Kupfer D. Dimensional psychopathology in offspring of parents with bipolar disorder. Bipolar Disord 2011: 13: 670–678.

Mood lability among offspring of parents with bipolar disorder and community controls

Early identification of bipolar disorder (BP) symptomatology is crucial for improving the prognosis of this illness. Increased mood lability has been reported in BP. However, mood lability is ubiquitous across psychiatric disorders and may be a marker of severe psychopathology and not specific to BP. To clarify this issue, this study examined the prevalence of mood lability and its components in offspring of BP parents and offspring of community control parents recruited through the Pittsburgh Bipolar Offspring Study.

Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder

This study aimed to identify neuroimaging measures associated with risk for, or protection against, bipolar disorder by comparing youth offspring of parents with bipolar disorder versus youth offspring of non-bipolar parents versus offspring of healthy parents in (i) the magnitude of activation within emotional face processing circuitry; and (ii) functional connectivity between this circuitry and frontal emotion regulation regions. The study was conducted at the University of Pittsburgh Medical Centre. Participants included 29 offspring of parents with bipolar disorder (mean age = 13.8 years; 14 females), 29 offspring of non-bipolar parents (mean age = 13.8 years; 12 females) and 23 healthy controls (mean age = 13.7 years; 11 females). Participants were scanned during implicit processing of emerging happy, sad, fearful and angry faces and shapes. The activation analyses revealed greater right amygdala activation to emotional faces versus shapes in offspring of parents with bipolar disorder and offspring of non-bipolar parents than healthy controls. Given that abnormally increased amygdala activation during emotion processing characterized offspring of both patient groups, and that abnormally increased amygdala activation has often been reported in individuals with already developed bipolar disorder and those with major depressive disorder, these neuroimaging findings may represent markers of increased risk for affective disorders in general. The analysis of psychophysiological interaction revealed that offspring of parents with bipolar disorder showed significantly more negative right amygdala-anterior cingulate cortex functional connectivity to emotional faces versus shapes, but significantly more positive right amygdala-left ventrolateral prefrontal cortex functional connectivity to happy faces (all P-values corrected for multiple tests) than offspring of non-bipolar parents and healthy controls. Taken together with findings of increased amygdala-ventrolateral prefrontal cortex functional connectivity, and decreased amygdala-anterior cingulate cortex functional connectivity previously shown in individuals with bipolar disorder, these connectivity patterns in offspring of parents with bipolar disorder may be risk markers for, rather than markers conferring protection against, bipolar disorder in youth. The patterns of activation and functional connectivity remained unchanged after removing medicated participants and those with current psychopathology from analyses. This is the first study to demonstrate that abnormal functional connectivity patterns within face emotion processing circuitry distinguish offspring of parents with bipolar disorder from those of non-bipolar parents and healthy controls.

Differences in sleep disturbances among offspring of parents with and without bipolar disorder: association with conversion to bipolar disorder

Disruptions in sleep and dysregulation in circadian functioning may represent core abnormalities in the pathophysiology of bipolar disorder (BP). However, it is not clear whether these dysfunctions are state or trait markers of BP. This report compared sleep and circadian phenotypes among three groups: offspring of parents with BP diagnosed with BP at intake (BP/OB; n = 47), offspring of parents with BP without BP at intake (non‐BP/OB; n = 386), and offspring of matched control parents who did not have BP (controls; n = 301). We also examined the association of baseline sleep parameters with subsequent development of BP among the non‐BP/OB group.