Successful Electroconvulsive Therapy in a Patient With Catatonia and Maternal Duplication 15q11-13 Syndrome.

ABSTRACT: The 15q11-q13 chromosomal region contains genes encoding for GABA-A receptor subunits and is a known region of epigenetic modification associated with the development of neurodevelopmental disorders. The presence of at least one additional copy of the maternal 15q11-q13 results in a syndrome (maternal dup15q) characterized by intellectual disability, autism spectrum disorder, mood disorders, and epilepsy. Catatonia is a serious syndrome of behavioral and motor dysfunction, which occurs across a variety of psychiatric, neurologic, and general medical conditions, which has successfully been treated with benzodiazepines and electroconvulsive therapy. In this case report, we describe the treatment course of a patient with established maternal dup 15q with comorbid intellectual disability, autism spectrum disorder, bipolar mood disorder, and juvenile epilepsy who developed hypokinetic catatonia refractory to high-dose benzodiazepine therapy. In contrast with benzodiazepine treatment, electroconvulsive therapy resulted in rapid improvement in catatonic symptoms and return to premorbid baseline. This case suggests that electroconvulsive therapy can be safely delivered for some patients with maternal dup 15q and may be rapidly effective when benzodiazepine treatment results in inadequate symptom improvement.

Maternal Duplication 15q11-13 Syndrome with Autism Spectrum Disorder: Mood Stabilization by Carbamazepine.

Objectives: Maternal 15q11-13 duplication syndrome (dup15q) is one of the most frequently observed and penetrant genetic abnormalities associated with autism spectrum disorder (ASD), and commonly presents with psychiatric symptoms and seizures. Although carbamazepine has been reported as effective in managing comorbid seizures in dup15q, it has not been reported to be used as a mood stabilizer in this population. Methods: We retrospectively reviewed the charts of five consecutive patients presenting with previously diagnosed dup15q and ASD seeking treatment for psychiatric symptoms and, in four of the patients, seizures. These were the only patients with dup15q treated with carbamazepine in the Neurodevelopmental Psychopharmacology Clinic at the University of Illinois at Chicago during the review period. Results: During treatment, carbamazepine was found to be more effective than other mood stabilizers in all five patients, and in one case a better antiepileptic. Symptoms consistent with bipolar mood disorder such as hyperactivity, impulsivity, irritability, mood lability, intrusiveness, and pressured speech were improved with carbamazepine in combination with other psychotropic medications. This improvement was greater than with other mood stabilizers, including oxcarbazepine, valproate, and lamotrigine. In one case, valproate paradoxically worsened symptoms. In three cases, anxiety was improved with carbamazepine when used in conjunction with other medications targeting anxiety. Conclusions: In treating five patients with dup15q, carbamazepine more effectively stabilized mood-related symptoms than alternative treatments. Prospective randomized controlled trials are necessary to confirm this observation.

De novo unbalanced translocation (4p duplication/8p deletion) in a patient with autism, OCD, and overgrowth syndrome.

Chromosomal abnormalities, such as unbalanced translocations and copy number variants (CNVs), are found in autism spectrum disorders (ASDs) [Sanders et al. (2011) Neuron 70: 863-885]. Many chromosomal abnormalities, including sub microscopic genomic deletions and duplications, are missed by G-banded karyotyping or Fragile X screening alone and are picked up by chromosomal microarrays [Shen et al. (2010) Pediatrics 125: e727-735]. Translocations involving chromosomes 4 and 8 are possibly the second most frequent translocation in humans and are often undetected in routine cytogenetics [Giglio et al. (2002) Circulation 102: 432-437]. Deletions of 4p16 have been associated with Wolf-Hirschhorn syndrome while 4p16 duplications have been associated with an overgrowth syndrome and mild to moderate mental retardation [Partington et al. (1997) Journal of Medical Genetics 34: 719-728]. The 8p23.3 region contains the autism candidate gene DLGAP2, which can contribute to autism when disrupted [Marshall et al. (2008) The American Journal of Human Genetics 82: 477-488] . There has been a case report of a family with autism spectrum disorder (ASD), prominent obsessional behavior, and overgrowth in patients with der (8) t (4;8) p (16;23) [Partington et al. (1997)]. This is an independent report of a male patient with autism, obsessive compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and an overgrowth syndrome, whose de novo unbalanced translocation der (8) t (4;8) p (16.1→ter; 23.1→ter) was initially missed by routine cytogenetics but detected with SNP microarray, allowing higher resolution of translocation breakpoints.

Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder.

BACKGROUND AND AIM: Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD. PARTICIPANTS AND METHODS: Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose. RESULTS: ABC-CV scores improved over the course of treatment (P<0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's<0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time. CONCLUSION: CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.

Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism.

OBJECTIVE: The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD). METHODS: Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses. RESULTS: Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p<0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups. CONCLUSIONS: Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study.

Post-traumatic stress disorder and its treatment in children and adolescents.

This article reviews current concepts of and treatments for post-traumatic stress disorder (PTSD) in children and adolescents. We discuss the DSM-IV-TR diagnostic criteria and their applicability to children and adolescents. We also review the history of PTSD and the development of its diagnostic criteria. We present the concept of complex trauma and trauma's effect on the developing child and describe a new diagnosis labeled developmental trauma disorder that would better describe children and adolescents who have been exposed to abuse and neglect. Finally, we summarize psychotherapeutic and psychopharmacologic approaches to treating PTSD in children and adolescents. More research is needed on the diagnosis and treatment of PTSD in children and adolescents.

Trends in psychotropic drug use in a child psychiatric hospital from 1991-1998.

OBJECTIVE: This study was undertaken to analyze inpatient prescribing patterns of psychotropic drugs in a child psychiatric hospital from 1991-1998. METHODS: Hospital pharmacy dispensing data were reviewed. Total admissions, first admissions, and readmissions were identified, and medication status of all patients at admission and at discharge was ascertained. Patterns of total psychotropic drug use and proportionate use of each drug class (antidepressants, mood stabilizers, antipsychotics stimulants, and alpha-2 antagonists) were evaluated. RESULTS: Controlling for the 2.3-fold rise in hospital admissions, there was a 73.0% increase in the use of psychotropic drugs from 1991-1998. The greatest relative increase was in the use of alpha-2 antagonists (from 3.3% to 23.6%). Significant increases were also observed for antidepressants (from 35.6% to 77.3%), mood stabilizers (from 14.9% to 32.6%), and stimulants (from 10.5% to 20.6%). Antipsychotic use showed no net change, although use of atypical agents largely supplanted that of conventional drugs. CONCLUSIONS: These findings document a marked and continuing increase in psychotropic drug use in child psychiatric inpatients during the 1990s. This trend occurred against a background of increased hospital admissions and shorter lengths of stay. Most of the increased use is accounted for by newer agents, even though data supporting their efficacy and safety in this population are limited.

An open-label study of citalopram in body dysmorphic disorder.

BACKGROUND: Body dysmorphic disorder (BDD), a preoccupation with an imagined or slight defect in appearance, is a relatively common and impairing disorder. While available data suggest that serotonin reuptake inhibitors are effective for BDD, investigation of this disorder's response to pharmacotherapy is limited, and there are no published reports on the efficacy of the selective serotonin reuptake inhibitor citalopram. In addition, there are no published reports on change in quality of life and multiple domains of psychosocial functioning with pharmacologic treatment for patients with BDD. METHOD: Fifteen subjects with DSM-IV BDD or its delusional variant were prospectively treated in a 12-week open-label trial of citalopram. Subjects were assessed at regular intervals with the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS; the primary outcome measure), the Clinical Global Impressions scale (CGI), the Brown Assessment of Beliefs Scale, measures of quality of life and multiple domains of psychosocial functioning, and other scales. Data were collected from Dec. 28, 1999, to March 1, 2001. RESULTS: On the BDD-YBOCS, scores decreased from a mean +/- SD of 30.7 +/- 4.9 at baseline to 15.3 +/- 10.6 at endpoint (p <.001), and 73.3% (N = 11) of subjects were responders. On the CGI, 40.0% of patients (N = 6) were very much improved, and 26.7% (N = 4) were much improved. Psychosocial functioning and mental health-related quality of life also significantly (p <.05) improved. The mean dose of citalopram was 51.3 +/- 16.9 mg/day, and the mean time to response was 4.6 +/- 2.6 weeks. Citalopram was generally well tolerated. CONCLUSION: Citalopram appears safe and effective for BDD. Psychosocial functioning and quality of life also significantly improved with citalopram.