Papers by Demitri Papolos
American Journal of Medical Genetics, 1996
Journal of clinical medicine, 2014
In children diagnosed with pediatric bipolar disorder (PBD), disturbances in the quality of sleep... more In children diagnosed with pediatric bipolar disorder (PBD), disturbances in the quality of sleep and wakefulness are prominent. A novel phenotype of PBD called Fear of Harm (FOH) associated with separation anxiety and aggressive obsessions is associated with sleep onset insomnia, parasomnias (nightmares, night-terrors, enuresis), REM sleep-related problems, and morning sleep inertia. Children with FOH often experience thermal discomfort (e.g. feeling hot, excessive sweating) in neutral ambient temperature conditions, as well as no discomfort during exposure to the extreme cold, and alternate noticeably between being excessively hot in the evening and cold in the morning. We hypothesized that these sleep- and temperature-related symptoms were overt symptoms of an impaired ability to dissipate heat, particularly in the evening hours near the time of sleep onset. We measured sleep/wake variables using actigraphy, and nocturnal skin temperature variables using thermal patches and a wir...
Journal of Neuroscience Research, 1991
Lithium salts are the most effective agents used in treating manic-depressive illness. It has bee... more Lithium salts are the most effective agents used in treating manic-depressive illness. It has been suggested that lithium's therapeutic efficacy could be due to an inhibitory effect on either inositol phospholipid (IP) and/or cyclic nucleotide metabolism. We have investigated the effect of lithium on these two signal transduction pathways in PC12 pheochromocytoma cells by studying a common effector target, expression of the fos protooncogene. We find that lithium, at therapeutic doses, has an augmenting effect on phosphatidylinositol (PI)-mediated fos expression induced by activating a muscarinic cholinergic pathway, whereas it has no effect, at tenfold the therapeutic dose, on fos expression induced by receptor or postreceptor activators of cyclic adenosine monophosphate (CAMP). The lithium augmenting effect is also observed when the cells are treated with phorbol esters, which directly activate protein kinase C (PKC), suggesting that the level of lithium's interaction with the IP pathway is at the postreceptor level. We also show that phorbol esters induce extensive down regulation of subsequent cholinergic and phorbol ester responsiveness as well as heterologous down regulation of CAMP responses. Treatment of downregulated cells with lithium leads to an enhanced responsiveness when cells are rechallenged with agonists that activate PKC but not by agonists that stimulate CAMP. We also show that carbamazepine, another antimanic agent, has an inhibitory effect on CAMP-mediated fos but no effect on the IP pathway. The opposite effects of lithium and carbamazepine on two critical transducing systems suggest a model for the antimanic action of these agents.
The American Journal of Human Genetics
Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate,... more Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate, learning disabilities, and characteristic facial appearance and is associated with hemizygous deletions within 22q11. A newly recognized clinical feature is the presence of psychiatric illness in children and adults with VCFS. To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, we evaluated 26 VCFS patients by clinical and molecular biological methods. The VCFS children and adolescents were found to share a set of psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients, >18 years of age, were affected with bipolar spectrum disorders. Four of six adult patients had psychotic symptoms manifested as paranoid and grandiose delusions. Loss-of-heterozygosity analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal d...
Molecular Psychiatry, 2001
Genes involved in the regulation of synaptic vesicle function are potential candidates for the de... more Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2,
The American journal of psychiatry, 1996
The purpose of this study was to conduct a systematic assessment of psychiatric illness in patien... more The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11. Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptom...
Background: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale ... more Background: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale of symptom dimensions frequently reported in childhood-onset bipolar disorder (BD) and scoring algorithms for DSM-IV BD, with and without attention- deficit/hyperactivity disorder (ADHD), and the proposed Narrow, Broad, and Core phenotypes. This report provides preliminary data on the reliability and validity of the CBQ. Method:
Psychiatry Research, 1996
Serotonergic systems have been implicated in the pathogenesis of major depression in humans as we... more Serotonergic systems have been implicated in the pathogenesis of major depression in humans as well as in learned helplessness (LH), an animal model of depression. To understand the significance of neuronal responses in depression and LH that are mediated by serotonin (5_hydroxytryptamine, SHT) receptors, we used intracerebroventricular injections to introduce a unique antisense oligonucleotide (ASO) to the 5HT,, receptor and determined its effect on LH behavior in Sprague-Dawley rats as determined by an escape-avoidance strategy. Of the rats injected with the 5HT,, receptor ASO, 8116 rats met criteria for LH. By contrast, only l/15 of the control group injected with 5HTrA sense oligonucleotide (SO) met criteria for LH. Quantitative receptor autoradiography revealed significant differences in 5HT,, receptor density between AS0 and control sense oiigonucieotides (SO), in close proximity to the injection site. Significant decreases in 5HTzA receptor density caused by oligonucleotide blockade were found in the CA3 hippocampal region. These data support the view that central 5HT, mediated by the 5HT2, receptor, participates in regulating behaviors that are affected by inescapable stress, and that the induction of behavioral depression may be specifically regulated via serotonergic pathways that terminate in this hippocampal subfield.
Psychiatric Genetics, 2005
To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps ... more 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. 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. 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. The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.
Psychiatric Genetics, 1996
Although research has focused primarily on the wide range of variability in the cognitive phenoty... more Although research has focused primarily on the wide range of variability in the cognitive phenotype between individuals with velo-cardiofacial syndrome (VCFS), we know relatively little about the extent to which within-individual expressions of the cognitive phenotype remain stable throughout development. General cognitive functioning in the low borderline range is the most consistent cognitive finding. Stronger reading decoding and spelling skills as well as auditory/verbal rote memory skills have been reported to be areas of relative strength. Conversely, significant visuospatial dysfunction, diminished math attainment, and executive dysfunction have all been reported as phenotypic. We propose several considerations that could advance our knowledge of developmental changes in the VCFS cognitive phenotype. The most salient of these is the need for more longitudinal designs with carefully matched control participants. ' 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:43-51.
Psychiatric Genetics, 1996
Wolters Kluwer Health may email you for journal alerts and information, but is committed to maint... more Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. ... Skip Navigation Links Home > Fall ...
Neuropsychobiology, 2006
The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One int... more 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. To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). 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. 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. These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ.
Molecular Psychiatry, 1998
Bipolar spectrum disorders are recurrent illnesses characterized by episodes of depression, hypom... more Bipolar spectrum disorders are recurrent illnesses characterized by episodes of depression, hypomania, mania or the appearance of mixed states. Great variability is evident in the frequency of episode recurrence and duration. 1-3 In addition to regular circannual episodes, 4 a spectrum of cycle frequencies has been observed, from the classical rapid cycling (RC) pattern of four or more episodes per year, 5,6 to those with distinct shifts of mood and activity occurring within a 24-48 h period, described as ultra-ultra rapid cycling (UURC) or ultradian cycling. 7-10 RC has a female preponderance, and occurs with greater frequency premenstrually, at the puerperium and at menopause. 11,12 Tricyclic antidepressants and MAOIs, both of which increase functional monoamines norepinephrine, dopamine and serotonin, are known to precipitate mania or rapid-cycling in an estimated 20-30% of affectively ill patients. We have recently reported a strong association between velo-cardio-facial syndrome (VCFS) patients diagnosed with rapid-cycling bipolar disorder, and an allele encoding the low enzyme activity catechol-O-methyltransferase variant (COMT L). 16,17 Between 85-90% of VCFS patients are hemizygous for COMT. 18 Homozygosity for the low activity allele (COMT LL) is associated with a 3-4 fold reduction of COMT enzyme activity compared with homozygotes for the high activity variant (COMT HH). 19,20 There is nearly an equal distribution of L and H alleles in Caucasians. 21 Individuals with COMT LL would be expected to have higher levels of transynaptic catecholamines due to a reduced COMT degradation of norepinephrine and dopamine. We therefore hypothesized that the frequency of COMT L would be greater in RC BPD ascertained from the general population. Significantly, we found that the frequency of COMT L was higher in the UURC variant of BPD than among all other groups studied (P = 0.002). These findings indicate that COMT L could represent a modifying gene that predisposes to ultra-ultra or ultradian cycling in patients with bipolar disorder.
Journal of Neuroscience Research, 1991
Lithium salts are the most effective agents used in treating manic-depressive illness. It has bee... more Lithium salts are the most effective agents used in treating manic-depressive illness. It has been suggested that lithium's therapeutic efficacy could be due to an inhibitory effect on either inositol phospholipid (IP) and/or cyclic nucleotide metabolism. We have investigated the effect of lithium on these two signal transduction pathways in PC12 pheochromocytoma cells by studying a common effector target, expression of the fos protooncogene. We find that lithium, at therapeutic doses, has an augmenting effect on phosphatidylinositol (PI)-mediated fos expression induced by activating a muscarinic cholinergic pathway, whereas it has no effect, at tenfold the therapeutic dose, on fos expression induced by receptor or postreceptor activators of cyclic adenosine monophosphate (CAMP). The lithium augmenting effect is also observed when the cells are treated with phorbol esters, which directly activate protein kinase C (PKC), suggesting that the level of lithium's interaction with the IP pathway is at the postreceptor level. We also show that phorbol esters induce extensive down regulation of subsequent cholinergic and phorbol ester responsiveness as well as heterologous down regulation of CAMP responses. Treatment of downregulated cells with lithium leads to an enhanced responsiveness when cells are rechallenged with agonists that activate PKC but not by agonists that stimulate CAMP. We also show that carbamazepine, another antimanic agent, has an inhibitory effect on CAMP-mediated fos but no effect on the IP pathway. The opposite effects of lithium and carbamazepine on two critical transducing systems suggest a model for the antimanic action of these agents.
Journal of Clinical and Experimental Neuropsychology, 2011
To determine the specificity of suggested endophenotypes of pediatric bipolar disorder (PBD), the... more To determine the specificity of suggested endophenotypes of pediatric bipolar disorder (PBD), the performance of 15 euthymic children with PBD was contrasted with that of 20 children with attention-deficit/hyperactivity disorder (ADHD), a population with reportedly similar executive dysfunction, and 18 children with both PBD and ADHD. Children with PBD and PBD+ADHD (ages 8 to 17) demonstrated higher intraindividual variability in reaction time, slower processing speed, and more sluggish motor preparedness than did children with ADHD. The findings support the contention that processing speed, intraindividual variability, and slower and more variable reaction time as interstimulus interval lengthens are likely specific endophenotypes of PBD.
Journal of Affective Disorders, 2013
Objectives: Intravenous ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, ha... more 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 6-19 years. 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.
Journal of Affective Disorders, 2006
Background: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale ... more Background: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale of symptom dimensions frequently reported in childhood-onset bipolar disorder (BD) and scoring algorithms for DSM-IV BD, with and without attentiondeficit/hyperactivity disorder (ADHD), and the proposed Narrow, Broad, and Core phenotypes. This report provides preliminary data on the reliability and validity of the CBQ. Method: Test-retest and inter-rater reliability of the CBQ were assessed. The ability of CBQ screening diagnoses and of the CBQ Core Index subscale to effectively predict diagnostic classification by structured interview was assessed using the K-SADS P/L. Results: Preliminary test-retest data showed excellent reliability for both the CBQ total score (r = 0.82) and the Core Index subscale (r = 0.86). Preliminary validity data was also promising. CBQ screening algorithms performed with a specificity of 97% and a sensitivity of 76% in classifying subjects with K-SADS P/L diagnosis of BD vs. no BD. The Core Index subscale had excellent agreement with K-SADS P/L diagnosis (k = 0.84) in classifying BD, ADHD-only, and no diagnosis and demonstrated 100% sensitivity and 86% specificity in classifying BD vs. no BD. Limitations: This preliminary data is from a sample enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse. Conclusions: The CBQ shows potential for rapid and economically feasible identification of possible childhood-onset BD cases as defined by DSM-IV criteria as well as by alternate disease phenotypes. Further validation studies will focus on inpatient and outpatient samples with a broader range of variability.
Journal of Affective Disorders, 2009
Background: In a prior concordance study of affected sibling pairs with a community diagnosis of ... more Background: In a prior concordance study of affected sibling pairs with a community diagnosis of pediatric bipolar disorder (PBD) a behavioral phenotype termed Fear of Harm (FOH) was found to have one of the strongest concordance coefficients (rho) between probands and siblings, and the widest contrasts between the rho-estimates for the proband/sibling vs. proband/comparison pairs . A strategy for identifying phenotypic subtypes: concordance of symptom dimensions between sibling pairs who met screening criteria for a genetic linkage study of childhood-onset bipolar disorder using the Child Bipolar Questionnaire (CBQ) was employed. J. Affect. Disord. 99,[27][28][29][30][31][32][33][34][35][36]. We used the Child Bipolar Questionnaire (OUT) (CBQ) to further elucidate this behavioral phenotype of PBD. We hypothesized that selective factors including parent reported symptoms of mania and depression, would be distinguishing features of impairment between groups defined by 1) the magnitude of their score on a continuous measure of FOH, and 2) the high FOH group would have significantly greater levels of severity on course of illness variables. These measures included earlier age of onset of first psychiatric symptoms, first hospitalization, and frequency of psychiatric hospitalizations, as well as, degree of social impairment as determined by exposure to the juvenile justice system and school performance problems. Methods: The sample was comprised of children with community diagnoses of bipolar disorder or at risk for the illness based on enriched family history with multiple first degree relatives diagnosed with BPD (N = 5335). Included were all subjects who had N 40 positively endorsed CBQ symptom items at frequencies of very often, almost always, and always. This group was divided randomly into two groups, the exploratory group (N = 2668) and the hypothesis testing (study) group (N = 2666). The exploratory group was used for the development of hypotheses and the study group was used to test these hypotheses on a new set of data. All results reported here derive from the latter group. In subsequent analyses, we classified each child as having a high degree of FOH, low FOH, or no FOH. We examined a subset of the sample for differences in age of onset of first psychiatric symptoms, course of illness and measures of symptom severity. These groups were compared using the chi-square procedure for categorical data and the Analysis of Variance (ANOVA) with Scheffe pair wise tests for continuous variables. The Child Bipolar Questionnaire V.2.0, the Yale-Brown Obsessive Compulsive Scale (YBOCS) and the Overt Aggression Scale (OAS) were the principal instruments used to obtain diagnostic information for this study. Results: We found that children representative of the FOH phenotype when compared to children with PBD who lack this trait had higher indices of severity of mania and depression, as well as other j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d indices that reflect severity and course of illness. Trait factors were derived from a factor analysis of CBQ in a large population of children diagnosed with or at risk for PBD, and used to further elucidate trait features of children with FOH. Children with the FOH traits were also more likely to be defined by six CBQ factors; Sleep/Arousal, Harm to Self and Others, Territorial Aggression, Anxiety, Self-esteem, Psychosis/Parasomnias/Sweet Cravings/Obsessions (PPSO). Limitations: This data is derived from samples enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse. Clinician diagnosis was not validated via research interview. Conclusions: The FOH phenotype, as defined by a metric derived from combining items from the YBOCS/OAS, is a clinically homogeneous behavioral phenotype of PBD with early age of onset, severe manic and depressive symptoms, and significant social impairment that is strongly associated with 6 CBQ factors and can be easily identified using the CBQ. Through the examination of dimensional features of PBD in an enriched sample of large size, we were able to further refine a phenotype and identify clinical dimensions potentially linked to endophenotypic markers that may prove fruitful in differential diagnosis, treatment and etiological studies of PBD. The nature of the sets of specific symptoms that comprise the FOH factors enabled us to propose a biological model for the phenotype (OUT) that involves a complex orexigenic circuit which links hypothalamic, limbic, and other brain nuclei primarily responsible for the regulation of behavioral and proposed physiological features of the FOH phenotype.
Human Molecular Genetics, 1994
Molecular Brain Research, 1992
It has been suggested that the therapeutic action of lithium in affective disorders may be due to... more It has been suggested that the therapeutic action of lithium in affective disorders may be due to its inhibition of signal transduction and second messenger synthesis, in particular of the phosphoinositide (PI) pathway. Yet, previous work in neuronal cell lines indicates that lithium has an enhancing effect on gene expression mediated by protein kinase C, which is activated by the PI pathway. In this report, we have analyzed the effect of lithium on two neuropeptide encoding genes that are regulated by second messenger systems; neuropeptide Y (NPY) and proenkephalin (Enk). We find that acute treatment with lithium, resulting in serum levels that are within the therapeutic range effective in patients with mood disorders, significantly enhances basal expression of the NPY gene in rat hippocampus~ In contrast, no effect on E:," expression was detected. This selective effect in a iimbic structure supports the hypothesis that gene expression may be an important target of lithium's therapeutic action.
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Papers by Demitri Papolos