Bipolar disorder in children: assessment in general pediatric practice.

PURPOSE OF REVIEW: Pediatricians are increasingly confronted with the mental health needs of children. Given the unanticipated role, well-described diagnostic guidelines and treatment protocols are essential: but often lacking. Identification of bipolar disorder in children, a condition which lacks diagnostic criteria consensus, presents a particular challenge. Despite this, it is generally regarded as a condition associated with considerable morbidity and mortality. Extended delays to treatment, typical for the condition, contribute to significantly reduced adult functionality. RECENT FINDINGS: Most children with bipolar disorder exhibit a subsyndromal course of illness. This has prompted many investigative groups to explore whether such a presentation is developmental or unique. Despite the ongoing debate, there has been a rapid increase in the rate of diagnoses. Concurrently, breakthroughs in neurology, neuroimaging, and genetics have called into question the existing conceptually based psychiatric constructs altogether. New research approaches which reflect these advances are more likely to lead to evidence-based diagnosis and treatment. Such an example is a novel phenotype called Fear of Harm (FOH). A new research perspective resulted in the unification of a broad range of symptoms from bipolar disorder as well as many of the co-occurring disorders. When considered as a whole, the syndrome maps on to a known neural pathway and has led investigators to a putative biomarker. SUMMARY: If given the right information and tools, pediatricians are uniquely positioned to interrupt the decline caused by mental illnesses. Importantly, the newly defined FOH syndrome includes clinical symptoms which are frequently first brought to the attention of pediatricians. Although these symptoms are not exclusive to the mood disorder, they could alert pediatricians to the need for further evaluation.

Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype.

OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. METHODS: A comparison was made between routinely collected symptom measures 1-2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6-19years. RESULTS: Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted.

Increase in GSK3beta gene copy number variation in bipolar disorder.

The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants.

Analysis of synapsin III-196 promoter mutation in schizophrenia and bipolar disorder.

BACKGROUND: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), -196G/A, has been identified in the promoter region. The -196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. OBJECTIVE: To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). METHODS: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the -196 SNP affected protein binding. RESULTS: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the -196 SNP binds to a brain protein in an allele-specific manner. CONCLUSIONS: These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ.

Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.

OBJECTIVE: To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. METHODS: The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case-control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. RESULTS: Homozygosity for a rare putative promoter variant, -1007C-->T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the -1007T allele compared with -1007C. CONCLUSION: The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.

BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.

Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.

Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P(2) are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12-linked PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9-intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12-linked psychiatric disorders.

Switching, cycling, and antidepressant-induced effects on cycle frequency and course of illness in adult bipolar disorder: a brief review and commentary.

The potential for the induction of mania, increased cycle frequency, and other behavioral adverse events associated with antidepressant exposure in patients with bipolar disorder is becoming an increasingly important area of research study, as this diagnosis receives wider recognition in youth. While the majority of studies in the adult literature, and much clinical experience suggest that precipitation of mania and cycle acceleration are common phenomenon, the retrospective nature of many of the published studies, different criteria for subject inclusion, and the application of statistical methods that are vulnerable to computational artifact, continue to raise some questions, and leave a number of methodological issues unresolved. This brief review of the adult literature addresses some of these key issues with the aim of encouraging further research in this area of clinical psychopharmacology.

Polymorphism screening of PIK4CA: possible candidate gene for chromosome 22q11-linked psychiatric disorders.

Lithium is potent non-competitive inhibitor of an enzyme involved in the metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P(2)), a critical phosphoinositide (PI) that regulates signal transduction and synaptic vesicle function. Interestingly, a number of genes involved in the regulation of PtdIns-4,5-P(2) synthesis and dephosphorylation are found in regions of the genome previously mapped in bipolar disorder (BPD) including 10p, 18q, 21q, and 22q. One is PIK4CA, a member of the phosphatidylinositol 4-kinase family that phosphorylates PtdIns at the D4 position of the inositol ring as part of the PtdIns-4,5-P(2) synthetic pathway. PIK4CA maps to 22q11 in a region believed to contain a susceptibility gene for psychiatric disorders. Screening of two functional domains of PIK4CA and the promoter region resulted in the identification of 15 different polymorphisms. Rare variants at a consensus splice donor site and the promoter region were found in a total of three patients with BPD, three with schizophrenia (SZ) and only one control. Several common non-synonymous changes and a common single nucleotide polymorphism (SNP) at position -31 in the putative promoter were identified and analyzed in patients with BPD, SZ, and controls. There was no difference in the allele distribution in mentally ill subjects and controls for two variants, R2259C and E2079Q, both located in the PIK4CA catalytic domain. There was, however, a trend toward significance in the distribution of the -31 promoter genotypes in bipolar subjects and controls. Although the results of this analysis were modest, considering the heterogeneity of BPD and SZ and the hypothesis that BPD may be caused by abnormalities in genes that regulate PI-mediated phenomena in the brain, the polymorphisms we detected in the PIK4CA gene should be analyzed in a larger data set to help determine their significance in 22q11-linked mental disorders.