Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

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.

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

Homeobox genes in obsessive-compulsive disorder.

BACKGROUND: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. METHODS: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. RESULTS: Three SNPs are most strongly associated with OCD: rs11854486 (P = 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P = 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P = 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. CONCLUSIONS: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.

Potential adverse effects of amphetamine treatment on brain and behavior: a review.

Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection is also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.

A screen of SLC1A1 for OCD-related alleles.

SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.

Obsessive-compulsive disorder: subclassification based on co-morbidity.

BACKGROUND: Obsessive-compulsive disorder (OCD) is probably an etiologically heterogeneous condition. Many patients manifest other psychiatric syndromes. This study investigated the relationship between OCD and co-morbid conditions to identify subtypes. METHOD: Seven hundred and six individuals with OCD were assessed in the OCD Collaborative Genetics Study (OCGS). Multi-level latent class analysis was conducted based on the presence of eight co-morbid psychiatric conditions [generalized anxiety disorder (GAD), major depression, panic disorder (PD), separation anxiety disorder (SAD), tics, mania, somatization disorders (Som) and grooming disorders (GrD)]. The relationship of the derived classes to specific clinical characteristics was investigated. RESULTS: Two and three classes of OCD syndromes emerge from the analyses. The two-class solution describes lesser and greater co-morbidity classes and the more descriptive three-class solution is characterized by: (1) an OCD simplex class, in which major depressive disorder (MDD) is the most frequent additional disorder; (2) an OCD co-morbid tic-related class, in which tics are prominent and affective syndromes are considerably rarer; and (3) an OCD co-morbid affective-related class in which PD and affective syndromes are highly represented. The OCD co-morbid tic-related class is predominantly male and characterized by high conscientiousness. The OCD co-morbid affective-related class is predominantly female, has a young age at onset, obsessive-compulsive personality disorder (OCPD) features, high scores on the 'taboo' factor of OCD symptoms, and low conscientiousness. CONCLUSIONS: OCD can be classified into three classes based on co-morbidity. Membership within a class is differentially associated with other clinical characteristics. These classes, if replicated, should have important implications for research and clinical endeavors.

A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families.

SLC1A encodes the neuronal and epithelial glutamate transporter and was previously tested as a candidate for obsessive-compulsive disorder (OCD) by several research groups. Recently, three independent research groups reported significant association findings between OCD and several genetic variants in SLC1A1. This study reports the results from a family-based association study, which examined the association between 13 single nucleotide polymorphisms (SNPs) within or in proximity to the SLC1A1 gene. Although we did not replicate association findings for those significant SNPs reported by previous studies, our study indicated a strong association signal with the SNP RS301443 (P-value = 0.000067; Bonferroni corrected P-value = 0.0167) under a dominant model, with an estimated odds ratio of 3.5 (confidence interval: 2.66-4.50). Further, we conducted single SNP analysis after stratifying the full data set by the gender status of affected in each family. The P-value for RS301443 in families with the male affected was 0.00027, and the P-value in families with female affected was 0.076. The fact that we identified a signal which was not previously reported by the other research groups may be due to differences in study designs and sample ascertainment. However, it is also possible that this significant SNP may be part of a regulator for SLC1A1, given that it is roughly 7.5 kb away from the boundary of the SLC1A1 gene. However, this potential finding needs to be validated biologically. Further functional studies in this region are planned by this research group.

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study.

SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had cortico-striatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.

Gender differences in genetic linkage and association on 11p15 in obsessive-compulsive disorder families.

Several clinical and genetic studies have reported gender differences in obsessive-compulsive disorder (OCD). Previously, we conducted a linkage genome scan using multipoint allele-sharing methods to test for linkage in 219 families participating in the OCD Collaborative Genetics Study. When these families were stratified by proband's gender, suggestive linkage to chromosome 11p15 at marker D11S2362 (KAC(all) = 2.92, P = 0.00012) was detected in families with male probands, but not in the ones with female probands. We have since conducted fine mapping with a denser microsatellite marker panel in the region of 11p15, and detected a significant linkage signal at D11S4146 (KAC(all) = 5.08, P < 0.00001) in the families of male probands. Subsequently, 632 SNPs were genotyped spanning a 4.0 Mb region of the 1 LOD unit interval surrounding the linkage peak in the original families and an additional 165 families. Six SNPs were associated with OCD (P < 0.001): two SNPs were identified when all the families were included, and four SNPs only in male proband families. No SNP showed significant association with the OCD phenotype only in the families with a female proband. The results suggest a possible gender effect in the etiology of OCD.

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

Dependent personality, separation anxiety disorder and other anxiety disorders in OCD.

BACKGROUND: The purpose of this study was to investigate whether dependent personality and/or general personality dimensions might explain the strong relationships between separation anxiety disorder (Sep-AD) and three other anxiety disorders (agoraphobia, panic disorder and social anxiety disorder) in individuals with obsessive compulsive disorder (OCD). METHODS: Using data from 509 adult participants collected during the OCD Collaborative Genetic Study, we used logistic regression models to evaluate the relationships between Sep-AD, dependent personality score, general personality dimensions and three additional anxiety disorders. RESULTS: The dependent personality score was strongly associated with Sep-AD and the other anxiety disorders in models adjusted for age at interview, age at onset of OC symptoms and worst ever OCD severity score. Several general personality dimensions, especially neuroticism, extraversion and conscientiousness, were also related to Sep-AD and the other anxiety disorders. Sep-AD was not independently related to these anxiety disorders, in multivariate models including general personality and dependent personality disorder scores. CONCLUSIONS: The results suggest that Sep-AD in childhood and these other anxiety disorders in adulthood are consequences of dependent personality disorder (for agoraphobia and panic disorder) or introversion (for social phobia). It is unknown whether these results would be similar in a non-OCD sample.

Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment.

BACKGROUND: Hyperactivity of the pituitary-adrenocortical axis is the most prominent neuroendocrine abnormality in major depression. It is state-related, returning to normal with resolution of the depressive episode. Adrenal gland enlargement also has been reported in patients with major depression and has been hypothesized as an index of cumulative lifetime depression. However, whether or not adrenal enlargement decreases with successful treatment of depression has not yet been studied, to our knowledge. We, therefore, determined adrenal gland volume in patients with major depression before and after treatment and in matched normal controls, and compared adrenal size with functional indexes of pituitary-adrenocortical activity. METHODS: Adrenal volumes were measured by magnetic resonance imaging in nine adult and two adolescent patients with major depression during their illness and during full remission when medication had been stopped for at least 1 month, and in nine adult and two adolescent normal control subjects individually matched to the patients. Basal, 4 to 7 PM plasma corticotropin 1-39 and cortisol levels, and corticotropin 1-39 and cortisol responses to administration of ovine corticorelin and lowdose cosyntropin also were measured. RESULTS: Mean adrenal gland volume was significantly larger, by about 70% in the patients while depressed than after successful treatment, and it also was significantly larger, again by about 70%, than the mean adrenal gland volume of their matched controls. After treatment, the mean adrenal volume of the patients decreased and was no longer significantly different from that of their controls at baseline. The magnitude of the decrease was significantly positively correlated with the duration of the depressive episode. Basal, late-afternoon plasma corticotropin 1-39 levels were significantly lower in the patients while depressed than in their matched controls, but basal plasma cortisol levels did not differ significantly among the three groups, nor did the corticotropin 1-39 and cortisol responses to corticorelin or the cortisol response to cosyntropin. Correlations between adrenal gland volume and basal corticotropin and cortisol levels, and the corticotropin and cortisol responses to hormone challenge, were not consistently in the expected direction in any of the three groups of subjects. CONCLUSIONS: Adrenal gland enlargement occurring during an episode of major depression appears to be state-dependent, in that it reverts to the normal size range during remission after treatment. It thus does not appear to be an index of cumulative lifetime depression. The lack of a discernible relationship between adrenal volume and pituitary-adrenocortical activity remains to be explained and might be related to noncorticotropin influences on the adrenal gland, including other tropic hormones and/or neural mechanisms.

Dose-dependent effects of scopolamine on nocturnal growth hormone secretion in normal adult men: relation to delta-sleep changes.

To explore the sensitivity of nocturnal GH secretion to different degrees of cholinergic blockade, we investigated the effects of two doses of the muscarinic receptor antagonist scopolamine (SCOP; 3.0 and 6.0 micrograms/kg, im) and placebo, administered in a randomized fashion at 2300 h on three nights to eight normal male volunteers. Both doses of SCOP produced significant reductions in mean nocturnal GH concentration compared to the effects of the placebo; the higher dose of SCOP reduced GH to a greater degree than the lower dose, but this difference was not statistically significant (mean, 2.3 micrograms/L after 6 micrograms/kg vs. 3.0 micrograms/L after 3 micrograms/kg). Both SCOP doses significantly shifted GH secretion into later portions of the night, with a significantly greater delay observed after the larger dose. Similarly, a significant delay in the time of the GH rise was produced by SCOP. In contrast, the effects of both doses of SCOP on delta-sleep or sleep onset were small. These data confirm earlier reports demonstrating that cholinergic muscarinic input represents a potentially important source of regulation of nocturnal GH release and suggest that the magnitude of the reduction in GH and the extent of delay in the GH rise time may reflect quantitative differences in the degree of cholinergic blockade. These data are in agreement with recent studies suggesting that the timing of GH release need not be associated with delta-sleep per se.

Sleep electroencephalographic abnormalities in adolescent depressives: effects of scopolamine.

In contrast to sleep studies of adult depressives that have consistently demonstrated abnormalities of sleep continuity, slow-wave sleep, and REM sleep, existing studies of depressed children and adolescents have been conflicting. Furthermore, only one study has explored the cholinergic regulation of sleep in early-onset depressives. In the present study, the electroencephalographic sleep of 20 adolescent outpatients with major depressive episodes and 13 normal control adolescents was obtained on two separate 2-night sessions, 1 night incorporating challenge with scopolamine. Depressed adolescents showed increased baseline phasic REM sleep measures, increased arousals, a trend toward reduced slow-wave sleep, and a greater difference in the change of first REM period density on the scopolamine night versus placebo night compared to controls. These findings support the continuity of some sleep abnormalities of depression into adolescence, and suggest that adolescent depression may be associated with alterations of cholinergic neurotransmission in some patients.

Adrenal gland volume in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function.

We measured adrenal gland volume and both baseline and stimulated pituitary and adrenal cortical hormones in 35 unmedicated, major depressives and 35 individually matched normal control subjects. Mean adrenal volume in the depressives was significantly larger, by about 38%, than the adrenal volume of their matched controls. Basal plasma adrenocorticotropic hormone (ACTH)1-39 was significantly lower, and basal plasma cortisol was significantly higher, in the patients. In contrast, basal plasma ACTH determined by radioimmunoassay (RIA) was not significantly different between the two groups. The ACTH response to ovine corticotropin-releasing hormone (oCRH), whether measured specifically as ACTH1-39 or by the less-specific RIA, was highly significantly lower in the depressives than in the controls. However, neither the cortisol response to oCRH nor its response to low-dose ACTH 1-24 differed significantly between groups. In both groups of subjects, correlations between adrenal gland volume and all the hormone measures were low, and none represented more than 4% shared variance. In the patients, adrenal volume did not correlate significantly with duration of the present episode, lifetime number of episodes, melancholic subtype, Hamilton Depression Scale total score, or the Hamilton suicidality item. However, adrenal volume was significantly positively related to the somatization factor of the Hamilton scale, which was almost totally accounted for by the specific items of somatic symptoms and somatic anxiety.

Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects.

The degree of cholinergic dysregulation of sleep in adult depression was evaluated using scopolamine. On separate sessions, placebo and scopolamine (4.5 micrograms/kg, IM) were administered to 14 patients with unipolar major depression, 16 recovered/remitted patients, and 18 normal controls. Scopolamine increased rapid eye movement (REM) latency (RL), reduced REM activity (RA), REM density (RD), and REM duration, and increased the percentage of stage 4 sleep in all groups. There was a differential effect of scopolamine on RL, RA, and REM duration for the first REM period, and on percentage of stage 4 sleep. Whereas a primary cholinergic hyperactivity could account for the RA and RD responses, the response profile for RL was more compatible with reduced aminergic tone as the proximal cause of the cholinergic hyperactivity. Whether the sleep abnormalities observed in remitted patients reflect an underlying vulnerability for development or recurrence of depression, and/or a scar, remains to be determined.