Betsy Zimerman

Double-Blind and Placebo-Controlled Study of Lithium for Adolescent Bipolar Disorders With Secondary Substance Dependency

OBJECTIVE To perform a double-blind, placebo-controlled, random assignment, parallel group, pharmacokinetically dosed study of lithium for adolescents with bipolar disorders (BP) and temporally secondary substance dependency disorders (SDD). METHOD Subjects were 16.3 +/- 1.2 years old and were comprehensively assessed during a 6-week outpatient protocol that included random weekly urine collection for drug assays and random and weekly serum collection for lithium levels. RESULTS Using both intent-to-treat (N = 25) and completer (n = 21) analyses, there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly random urine drug assays. The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD. Mean age at onset of BP was 9.6 +/- 3.9 years and of SDD was 15.3 +/- 1.3 years. There were multigenerational mood disorders in 96% and multigenerational SDD in 56% of families. CONCLUSIONS Lithium treatment of BP with secondary SDD in adolescents was an efficacious treatment for both disorders. These results warrant replication with a long-term maintenance phase. The mean 6-year interval between the onset of BP and onset of SDD strongly argues for earliest recognition of BP.

DSM-IV mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype compared to attention-deficit hyperactive and normal controls.

OBJECTIVE To compare the prevalence of Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) mania symptoms in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) to those with attention deficit hyperactivity disorder (ADHD) and normal community controls (CC). METHODS To optimize generalizeability, subjects with PEA-BP and ADHD were consecutively ascertained from outpatient pediatric and psychiatric sites, and CC subjects were obtained from a random survey. All 268 subjects (93 with PEA-BP, 81 with ADHD, and 94 CC) received comprehensive, blind, baseline research assessments of mothers about their children and of children about themselves. PEA-BP was defined by DSM-IV mania with elation and/or grandiosity as one criterion to ensure that subjects had one of the two cardinal symptoms of mania and to avoid diagnosing mania only by criteria that overlapped with those for ADHD. RESULTS Five symptoms (i.e., elation, grandiosity, flight of ideas/racing thoughts, decreased need for sleep, and hypersexuality) provided the best discrimination of PEA-BP subjects from ADHD and CC controls. These five symptoms are also mania-specific in DSM-IV (i.e., they do not overlap with DSM-IV symptoms for ADHD). Irritability, hyperactivity, accelerated speech, and distractibility were very frequent in both PEA-BP and ADHD groups and therefore were not useful for differential diagnosis. Concurrent elation and irritability occurred in 87.1% of subjects with PEA-BP. Data on suicidality, psychosis, mixed mania, and continuous rapid cycling were also provided. CONCLUSION Unlike late teenage/adult onset bipolar disorder, even subjects with PEA-BP selected for DSM-IV mania with cardinal symptoms have high rates of comorbid DSM-IV ADHD. High rates of concurrent elation and irritability were similar to those in adult mania.

Diagnostic Characteristics of 93 Cases of a Prepubertal and Early Adolescent Bipolar Disorder Phenotype by Gender, Puberty and Comorbid Attention Deficit Hyperactivity Disorder

OBJECTIVE Etiopathogenetic and treatment studies require homogeneous phenotypes. Therefore, effects of gender, puberty, and comorbid attention deficit hyperactivity disorder (ADHD) on DSM-IV mania criteria and other characteristics of a prepubertal and early adolescent bipolar disorder (PEA-BP) phenotype were investigated. METHOD Consecutively ascertained PEA-BP (with or without comorbid ADHD) outpatients (n = 93) were blindly assessed by research nurses with comprehensive instruments given to mothers and children separately, consensus conferences, and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one criterion and to be definite cases by severity ratings. RESULTS Subjects were aged 10.9 +/- 2.6 years, had current episode length of 3.6 +/- 2.5 years, and had early age of onset at 7.3 +/- 3.5 years. No significant differences were found by gender, puberty, or comorbid ADHD on rates of mania criteria (e.g., elation, grandiosity, racing thoughts), mixed mania, psychosis, rapid cycling, suicidality, or comorbid oppositional defiant disorder (ODD), with few exceptions. Subjects with comorbid ADHD were more likely to be younger and male. Pubertal subjects had higher rates of hypersexuality. CONCLUSIONS These findings support that the PEA-BP phenotype is homogeneous except for differences (hyperactivity, hypersexuality) that mirror normal development.

Lithium for prepubertal depressed children with family history predictors of future bipolarity: a double-blind, placebo-controlled study

BACKGROUND Because of negative studies of TCAs for prepubertal major depressive disorder (PMDD) and because of the potentially high switch rate of PMDD to prepubertal bipolarity (BP), it was hypothesized that lithium would be efficacious treatment for PMDD in children who also had family history (FH) predictors of future BP. METHODS A double-blind, placebo-controlled, and pharmacokinetically dosed study of lithium for PMDD with FH predictors of future BP was performed. Random assignment was stratified by FH of BP-I or mania versus loaded/multigenerational (L/M) FH of MDD without BP-I or mania. Comprehensive assessments were done during a six week outpatient protocol that included weekly serum lithium levels. RESULTS Mean age was 10.7+/-1.2 years; 17 subjects were randomized to active and 13 to placebo; 80% had FH of BP-I or mania (40% of parents had BP-I or mania); and 20% had FH of L/M MDD. Using both intent to treat with last observation carried forward (n = 30) and completer (n = 24) analyses, there were no significant differences on continuous or categorical measures between active and placebo groups. Mean serum lithium level was 0.99+/-0.16 mEq/l. There were no significant differences between mean total daily dose or mean serum lithium levels between responders and non-responders. LIMITATIONS Four subjects on active drug were discontinued because of dose-limiting side effects (three were cognitive impairment). Future studies of treatment for PMDD should consider alternative drugs. CLINICAL RELEVANCE Lithium was not significantly more efficacious than placebo for PMDD with FH predictors of future BP.

Six-Month Stability and Outcome of a Prepubertal and Early Adolescent Bipolar Disorder Phenotype

OBJECTIVE Six-month follow-up data are provided on a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP). Stabilities were defined as continuous presence of PEA-BP and of individual mania criteria between baseline and 6 months. METHOD Baseline and 6-month assessments of consecutively ascertained PEA-BP outpatients (n = 91) included comprehensive instruments given to mothers and children, separately, by research nurses; consensus conferences; and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one mania criterion and to be definite cases by severity ratings. RESULTS Of the 93 baseline subjects, 91 completed the 6-month assessment, for a retention rate of 97.8%. Baseline age was 10.9 +/- 2.7 years, and age of onset of current episode was 7.3 +/- 3.5 years. At 6 months, 85.7% still had full criteria and severity for mania or hypomania, and only 14.3% had recovered. Six-month stabilities of elated mood and grandiosity were high. Cox modeling and logistic regression did not show any significant effect of multiple covariates (e.g., gender, puberty, psychosis, mixed mania, rapid cycling, or naturalistic treatment). CONCLUSIONS These longitudinal stability findings provide validation of a PEA-BP phenotype. Poor outcome was consistent with similarity of PEA-BP baseline characteristics to those of treatment-resistant adult-onset mania.

Temperament and Character Factors in a Prepubertal and Early Adolescent Bipolar Disorder Phenotype Compared to Attention Deficit Hyperactive and Normal Controls

OBJECTIVE To compare temperament and character (T/C) factors in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP), attention deficit hyperactivity disorder (ADHD), and normal community controls (NC). METHODS Subjects in PEA-BP (n = 101), ADHD (n = 68), and NC (n = 94) groups were diagnostically assessed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia given separately to mothers about their children and to children about themselves. Diagnosis of PEA-BP was defined as Diagnostic and Statistical Manual of Mental Disorders, fourth edition, bipolar disorder (manic or mixed phase) with at least one cardinal symptom of mania (i.e., elation and/or grandiosity) to avoid diagnosing mania by symptoms that overlapped with those for ADHD. The Junior Temperament and Character Inventory (JTCI) was used to measure T/C factors. Separate JTCI data were obtained from mothers about their children and from children about themselves. RESULTS Parent- and child-reported novelty seeking were significantly higher in PEA-BP than in NC subjects. Novelty seeking was significantly higher in the ADHD group than in the NC group only by parent report. Parent and/or child report showed PEA-BP and ADHD subjects to be significantly less reward-dependent, persistent, self-directed, and cooperative than NC subjects. Parent-reported cooperativeness was significantly lower in PEA-BP than in ADHD subjects. CONCLUSION These findings are consistent with studies of novelty seeking in adults who had either BP or ADHD and are discussed in relationship to genetic studies of dopamine receptors and novelty seeking.