Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Genetic and imaging strategies in obsessive-compulsive disorder: potential implications for treatment development.

In recent years, advances in brain research have resulted in a striking strategic shift in studies designed to develop new, effective treatments for neuropsychiatric disorders. This involves a multidisciplinary approach with recursive interactions among respective disciplines with the ultimate goal of contributing to treatment development. In this review we focus on treatment implications of brain imaging and molecular and pharmacogenetic studies in obsessive-compulsive disorder. Translational components of this research are addressed, including the potential for integrating advances in brain imaging and molecular and pharmacogenetic assessments as they may potentially relate to neurodiagnostic assessment and treatment development. Studies of putative susceptibility alleles in obsessive-compulsive disorder involving the serotonergic, glutamatergic, and dopaminergic systems may provide a focus for these divergent approaches. Taken together, neuroimaging and genetic methods may ultimately lead to a mechanistic understanding of the pathogenesis and maintenance of neuropsychiatric disorders such as obsessive-compulsive disorder that may, in turn, result in the development of new neurodiagnostic and treatment approaches.

Whole blood serotonin in juvenile obsessive-compulsive disorder.

Whole blood serotonin (5-HT) concentration was assessed in 16 children and adolescents with severe obsessive-compulsive disorder (OCD) and in 14 normal adolescent controls. There was no difference in blood 5-HT content between the OCD patients and the normal controls. However, the OCD patients with a family history of OCD had significantly higher blood 5-HT levels than did either the OCD patients without a family history of OCD or the normal controls. Blood 5-HT content was not associated with a history of major depressive disorder or chronic tic disorder. These preliminary results suggest that studies of serotonergic functioning in OCD may need to control for family history of OCD and that blood 5-HT may be a useful biochemical measure in family-genetic studies of OCD.

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis.

BACKGROUND: Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS: Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS: After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS: A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.

Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with the l/l genotype. Further studies of the regulation of HTT gene expression are indicated.

Demographic and clinical features of obsessive-compulsive disorder in children and adolescents.

OBJECTIVE: To describe the demography, symptomatology, and comorbidity of 31 clinically referred children and adolescents with obsessive-compulsive disorder. METHOD: The patients were assessed in an outpatient clinic for lifetime psychopathology with the Diagnostic Interview for Children and Adolescents. The child and adolescent version of the Yale-Brown Obsessive Compulsive Scale (CY-BOCS) was used to group obsessive-compulsive symptoms and rate symptom severity. Demographic, medical, developmental, academic, and behavioral information was recorded by the parents in the Yale Children's Inventory and the Child Behavior Checklist. RESULTS: The male-female ratio was approximately 3:2. Most patients had had multiple obsessions and compulsions that had changed over time. The CY-BOCS correlated highly with another measure of obsessive-compulsive behavior, but not with any of the Child Behavior Checklist scales. Symptom severity was influenced by an interaction between gender and age at onset of the illness. More than 80% of the subjects had other lifetime psychiatric diagnoses. CONCLUSIONS: The results provide further evidence that obsessive-compulsive disorder is a chronic, severe illness in children and adolescents that is often associated with other forms of psychopathology. The data support the concurrent and discriminant validity of the CY-BOCS.

Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder.

OBJECTIVE: The study was conducted with children and adolescents with obsessive-compulsive disorder (OCD) to assess the relationship of whole blood serotonin (5-HT) content to a concurrent diagnosis of a disruptive behavior disorder (DBD) and to severity ratings of aggressive behavior. METHOD: Eighteen children and adolescents who met DSM-III-R criteria for OCD were evaluated with a structured interview, clinician rating scales, and the Child Behavior Checklist (CBCL). Blood 5-HT concentration was assayed with a fluorometric procedure. Relationships among categorical diagnoses, dimensional ratings, and blood 5-HT content were analyzed with bivariate and multivariate techniques. RESULTS: OCD subjects with a DBD (n = 6) had significantly higher scores than those without a DBD (n = 12) on the Total Problem scale, the Externalizing Problem scale, and several of the behavioral syndrome scales of the CBCL. Blood 5-HT concentrations were significantly lower in those with a DBD than in those without a DBD, and blood 5-HT concentrations had significant negative correlations with the Total score, the Externalizing score, and the Aggressive Behavior score of the CBCL. CONCLUSIONS: The results provide further evidence of a significant relationship between aggressive behavior and serotonergic functioning.

Prolactin in childhood obsessive-compulsive disorder: clinical correlates and response to clomipramine.

Basal prolactin concentrations were measured before treatment in 18 children and adolescents with obsessive-compulsive disorder as well as in 15 of these patients after 4 and 8 weeks of clomipramine treatment. Basal prolactin levels were influenced by a history of chronic tic disorder and by the duration and severity of obsessive-compulsive symptoms. Clomipramine administration significantly increased basal prolactin levels. A slight decline in prolactin levels during the last 4 weeks of clomipramine treatment was positively correlated with a favorable treatment response and negatively correlated with duration of illness. If the changes in prolactin levels observed during clomipramine treatment are due primarily to changes in serotonergic neurotransmission, these data suggest that clomipramine treatment of obsessive-compulsive disorder produces an adaptive decrease in the responsiveness of serotonergic receptors.

Aggressive behavior in clinically depressed adolescents.

OBJECTIVE: To investigate the prevalence and characteristics of aggressive behavior in adolescent inpatients and outpatients with major depressive disorder (MDD). Differences between males and females in prevalence and type of aggression, and level of parent-child agreement in report of aggression, were analyzed. METHOD: Participants were 74 adolescents with MDD, aged 13 to 17 years. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to identify MDD. Adolescents' aggressive behavior was assessed using an adapted version of the Brown-Goodwin Assessment for Lifetime History of Aggression; the Measure of Aggression, Violence, and Rage in Children; and the Buss-Durkee Hostility Inventory-Adapted Version. RESULTS: Results indicate high levels of aggressive behavior in adolescents with MDD. Amount and type of aggression did not differ by gender. Results indicate poor correspondence between parent and adolescent reports of aggression, which was most marked for females. CONCLUSIONS: Aggressive behaviors are highly prevalent in depressed youths, with similar types and levels evident in males and females. Parents tend to under-report and may not be cognizant of aggressive behavior that occurs outside the home, particularly for females.

Urinary catecholamine excretion and behavioral differences in ADHD and normal boys.

Urinary catecholamine excretion was assessed in 15 boys with attention-deficit/hyperactivity disorder (ADHD) and 16 normal controls during a defined physical and mental task. Dihydroxyphenylalanine, dopamine, norepinephrine (NE), epinephrine (EPI), 3,4-dihydroxyphenylacetic acid, and 3,4-dihydroxyphenylglycol (DOPEG) concentrations were assayed by high-pressure liquid chromatography with electrochemical detection. The urinary concentration of DOPEG, an NE metabolite that has not been previously measured in ADHD, was significantly lower in the ADHD subjects than in the normal controls. There was also a trend for lower urinary EPI levels in the hyperactive boys. Stepwise multiple regression analyses demonstrated that DOPEG and EPI each contributed significantly to the variance in the behavioral symptoms within the full sample. The results are consistent with previous reports of abnormal metabolism of norepinephrine and epinephrine in ADHD. These neurochemical findings may be due to differences between ADHD and normal boys in neuronal (central or peripheral) or nonneuronal (e.g., adrenal, renal) activity. The results are also consistent with prior findings in normal children of an inverse relationship between EPI excretion and inattentive, restless behaviors. Together, these findings suggest caution in ascribing metabolite changes to ADHD or to ADHD-like behaviors that may be seen in normal children.

Buspirone treatment of anxiety associated with pharyngeal dysphagia in a four-year-old.

Buspirone is a nonbenzodiazepine anxiolytic that has been effective in uncontrolled trials for treating childhood anxiety disorders. A 4-year-old boy with a history of laryngomalacia (congenital structural abnormality with airway collapse and obstruction on inhalation), pharyngeal dysphagia (difficulty in swallowing), poor weight gain, delayed self-feeding skills, and anxiety symptoms is described. An open trial of buspirone, increased gradually to 12.5 mg daily in divided doses over a period of 22 weeks, was associated with decreased anxiety, improved self-feeding skills, and weight gain. Based on parental reports, buspirone appeared to decrease separation and social anxiety, as well as anxiety associated with eating. Drug discontinuation was associated with symptom relapse, whereas drug readministration lead to the same clinical benefits that had been observed previously. The medication was well tolerated, and its benefits have persisted for over 1 year. No new recommendations can be made regarding the use of buspirone in preschool children or in the treatment of anxious behaviors adversely affecting medical conditions in children and adolescents.

Separation anxiety in children and adolescents treated with risperidone.

Risperidone is an atypical antipsychotic that has been investigated as a treatment for several severe psychiatric disorders in children and adults. A low dose of risperidone was added to other medications to treat two adolescent boys with obsessive compulsive disorder (OCD) and a childhood history of separation anxiety disorder, and one prepubertal boy with a history of attention deficit hyperactivity disorder and escalating behavior suggestive of mania. Each patient developed severe separation anxiety that resolved when risperidone was discontinued. The response was similar to that described in Tourette's disorder patients treated with haloperidol and pimozide. Two of the patients were treated subsequently with olazapine without a recurrence of separation anxiety. We discuss the diagnostic issues concerning separation anxiety induced by antipsychotic medications, and suggest that the atypical antipsychotics may differ in their tendency to elicit separation anxiety.

Stimulant medication and reading performance: follow-up on sustained dose in ADHD boys with and without conduct disorders.

The study examined the sustained effects of methylphenidate on reading performance in a sample of 42 boys, aged 8 to 11, with attention deficit-hyperactivity disorder (ADHD). Two subgroups were formed based on the presence or absence of co-occurring conduct disorders. Subjects were selected on the basis of their positive response to methylphenidate as determined in a series of original medication trials (Forness, Cantwell, Swanson, Hanna, & Youpa, 1991). For the purpose of this study, subjects were placed on their optimal dose of medication for a 6-week period and then tested on measures of oral reading and reading comprehension equivalent to those used in the original trials, retested after a week without medication (placebo), then tested again the following week after return to medication. Only the subgroup with conduct disorders responded, and this response was limited to reading comprehension improvement in only those subjects who also demonstrated improvement in oral reading on original trials. No response differences were found between subjects with or without learning disabilities.

Differential effects of stimulant medication on reading performance of boys with hyperactivity with and without conduct disorder.

Controversy surrounding stimulant medication, particularly its effects on reading performance, continues to obscure the issue of the use of this drug in classroom situations. The present study emphasized careful differential diagnosis, double-blind and placebo approaches, and curriculum-based dependent measures to address these concerns. Methylphenidate was administered to two groups of boys, ages 8 through 11. The two groups included 27 subjects meeting criteria for attention deficit-hyperactivity disorder but not conduct disorder, known as hyperactive disorder (HD), and 28 subjects meeting criteria for both diagnostic categories, known as hyperactive-aggressive (HA). Only four subjects in each group met a discrepancy criterion for learning disabilities (LD). Methylphenidate was administered to both groups at three levels of dosage, along with baseline and placebo conditions. Dependent measures involved both reading recognition and reading comprehension, equivalent across all conditions. No significant results were found for the group with HD in either reading recognition or comprehension, due largely to unusual placebo reactions. Results were generally in the direction predicted for the group with HA, but only significantly so in reading comprehension, and no dose effect was found on this variable. Implications for reading as a dependent measure of medication effects are discussed.

Trichotillomania and related disorders in children and adolescents.

Eleven chronic hair pullers, 11 subjects with obsessive-compulsive disorders (OCD), and 11 subjects with a non-OCD anxiety disorder were assessed with structured interviews and the Child Behavior Checklist (CBCL). Only 4 hair pullers (36%) reported both rising tension and relief with hair pulling. Each group had significantly more internalizing than externalizing symptoms on the CBCL. Seven hair pullers (64%) had a lifetime history of at least one other axis I diagnosis. The results provide further evidence that trichotillomania in referred children and adolescents is usually a chronic disorder often associated with internalizing symptoms and psychiatric comorbidity. Rising tension followed by relief with hair pulling may be an unnecessary restriction in the diagnosis of childhood trichotillomania.

Prestimulation-induced startle modulation in attention-deficit hyperactivity disorder and nocturnal enuresis.

Startle modulation was induced by prestimulation in 43, 6-11 year old boys with attention-deficit hyperactivity disorder (ADHD), 13 of whom were or had been enuretic, 17 age-matched enuretic boys, and 42 age-matched normal boys, using 60-ms and 120-ms prestimulation intervals and a 4000-ms continuous tone. There was a significant multivariate effect of enuresis on startle amplitude modulation. This effect was attributed primarily to the reduction of amplitude inhibition following the 120-ms prestimulation interval regardless of whether or not enuresis was associated with ADHD. There was no effect of ADHD on startle modulation by prestimulation. The inhibition following the 120-ms prestimulation interval in the enuretic boys was reduced to the level of 5-year-old normal children, suggesting a maturational component of the deficient startle inhibition. The neurophysiologic dysfunction underlying the deficient startle inhibition in enuresis, but not ADHD, is discussed in terms of a possible dysfunction of mesopontine reticular mechanisms mediating preattentive processing of signals associated with spinal reflexes involved in urinary bladder control.

S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: preliminary results from an open trial.

The psychostimulants d-amphetamine and methylphenidate are thought to be the most effective treatment in children, adolescents, and adults with attention deficit-hyperactivity disorder (ADHD) because they potentiate both dopamine (DA) and norepinephrine (NE) at the synaptic cleft. These medications are not free from side effects and controversy. Newer effective and safe treatments are needed. S-Adenosyl-L-methionine (SAM), the active form of methionine, acts as a methyl donor and is involved in many metabolic pathways. It has beta adrenergic and DA receptor agonist activity. We have been using oral SAM in a sample of well-diagnosed adults with ADHD, residual state (RS) in a 4-week open trial to establish SAM effectiveness and safety and in a 9-week, double-blind, placebo-controlled crossover trial. Preliminary data from the open trial reveal that 75 percent (6 out of 8 male) patients improve on it. The 2 who did not improve had not improved on methylphenidate trial. Improvement ranged from moderate to marked, with minimal and transient side effects that did not interfere with functioning.

Nomifensine maleate in adult attention deficit disorder.

The authors studied 18 adults (8 men and 10 women) in an open trial of nomifensine maleate for the treatment of attention deficit disorder (ADD). All patients met DSM-III criteria and the Utah criteria for ADD, residual type (RT). Medication effect was measured at week 1 and week 4 of treatment using the Structured Interview for ADD-H Symptoms. Data from week 4 showed that all eight men and seven of the women responded well to nomifensine, showing a significant decrease in ADD with hyperactivity symptoms. Side effects were minimal, consisting of drowsiness, dry mouth, headache, and nausea. One responder (5%) was taken off the medicine after developing an allergic reaction. Results showed that short-term use of nomifensine was relatively free from side effects and was remarkably effective in the treatment of ADD-RT. The authors discussed the implications of the use of nomifensine and related drugs in the treatment of ADD-RT.