A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

Meta-analysis: hoarding symptoms associated with poor treatment outcome in obsessive-compulsive disorder.

DSM-5 recognizes hoarding disorder as distinct from obsessive-compulsive disorder (OCD), codifying a new consensus. Hoarding disorder was previously classified as a symptom of OCD and patients received treatments designed for OCD. We conducted a meta-analysis to determine whether OCD patients with hoarding symptoms responded differently to traditional OCD treatments compared with OCD patients without hoarding symptoms. An electronic search was conducted for eligible studies in PubMed. A trial was eligible for inclusion if it (1) was a randomized controlled trial, cohort or case-control study; (2) compared treatment response between OCD patients with and those without hoarding symptoms, or examined response to treatment between OCD symptom dimensions (which typically include hoarding) and (3) examined treatment response to pharmacotherapy, behavioral therapy or their combination. Our primary outcome was differential treatment response between OCD patients with and those without hoarding symptoms, expressed as an odds ratio (OR). Twenty-one studies involving 3039 total participants including 304 with hoarding symptoms were included. Patients with OCD and hoarding symptoms were significantly less likely to respond to traditional OCD treatments than OCD patients without hoarding symptoms (OR=0.50 (95% confidence interval 0.42-0.60), z=-7.5, P<0.0001). This finding was consistent across treatment modalities. OCD patients with hoarding symptoms represent a population in need of further treatment research. OCD patients with hoarding symptoms may benefit more from interventions specifically targeting their hoarding symptoms.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder.

We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed-doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD.

Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex.

Little is known about regionally specific signals that control the number of neuronal progenitor cells in vivo. We have previously shown that the germline mutation of the basic fibroblast growth factor (Fgf2) gene results in a reduction in the number of cortical neurons in the adult. We show here that Fgf2 is expressed in the pseudostratified ventricular epithelium (PVE) in a dorsoventral gradient and that Fgf2 and its receptor, Fgfr-1, are downregulated by mid to late stages of neurogenesis. In Fgf2 knockout mice, the volume and cell number of the dorsal PVE (the cerebral cortical anlage) are substantially smaller, whereas the volume of the basal PVE is unchanged. The dorsal PVE of Fgf2 knockout mice has a 50% decrease in founder cells and a reduced expansion of the progenitor pool over the first portion of neurogenesis. Despite this reduction, the degree of apoptosis within the PVE is not changed in the Fgf2 knockouts. Cortical neuron number was decreased by 45% in Fgf2 knockout mice by the end of neurogenesis, whereas the number of neurons in the basal ganglia was unaffected. Microscopically, the frontal cerebral cortex of neonatal Fgf2 null mutant mice lacked large neurons in deep cortical layers. We suggest that Fgf2 is required for the generation of a specific class of cortical neurons arising from the dorsal PVE.

Depression and anxiety disorders in parents and children. Results from the Yale family study.

The children (aged 6 to 17 years) of probands with primary major depression, with and without various anxiety disorders, were compared with the children of a matched normal control group. The results from the study of these young children parallel our previous findings among the adult first-degree relatives of these probands. Depression in the proband increased the risk of depression in the children. Depression plus panic disorder or agoraphobia in the proband conferred an additional risk of depression and of an anxiety disorder in the children. Panic disorder in the parents conferred more than a threefold increased risk of separation anxiety in the children. Other factors that increased the risk to children were degree of familial loading for psychiatric illness, parental assortative mating, and parental recurrent depression. The findings suggest a relationship between depression and some of the anxiety disorders, and between adult panic disorder and agoraphobia and transmission of anxiety disorders to children.

Plasma free and conjugated MHPG in psychiatric patients. A pilot study.

Measures of plasma 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) may be useful for investigating noradrenergic function in certain behavioral and physiologic states. Serial plasma and urine samples were obtained from a diagnostically heterogeneous group of ten psychiatric inpatients over a three- to five-day period. The plasma samples were assayed for free and total MHPG and the urine samples for total MPHG. The variance between patients in both plasma free and conjugated MHPG was markedly greater than the variance within patients. The test-retest reliability for free plasma MHPG in both AM vs PM values within and across study days was also significant for both free and conjugated MHPG even though the AM plasma free MHPG values were significantly greater than the PM values. No significant correlations were found between plasma free and conjugated MHPG or between urinary total MHPG and plasma free MHPG.

Reduced MAO activity in first-degree relatives of individuals with bipolar affective disorders. A preliminary report.

Previous reports have indicated that platelet monoamine oxidase (MAO) activity is reduced in patients with the bipolar form of major affective illness. We present evidence that platelet MAO activity is also significantly reduced in the first-degree relatives of bipolar patients. However, platelet MAO activity did not distinguish ill from well family members. It is possible that reduced platelet MAO may be an indicator of increased familial vulnerability to affective disorders.

Best estimate of lifetime psychiatric diagnosis: a methodological study.

It is important for genetic, epidemiologic, and nosological studies to determine accurate rates of lifetime psychiatric diagnoses in patient and nonpatient populations. As part of a case-control family study of major depression, lifetime psychiatric diagnoses were made for 1,878 individuals. Sources of information used in making diagnostic estimates included direct interview, medical records, and family history data systematically obtained from relatives. Diagnostic estimates were made by trained interviewers, experienced clinicians, and by computer program. The results indicate that it is possible to make lifetime best estimate diagnoses reliably among both interviewed and noninterviewed individuals for most diagnostic categories and that diagnoses based on interview data alone are an adequate substitute for best estimate diagnoses based on all available information in a limited number of diagnostic categories.

Rebound phenomena in Tourette's syndrome after abrupt withdrawal of clonidine. Behavioral, cardiovascular, and neurochemical effects.

Following an open trial of clonidine hydrochloride (3 to 8 micrograms/kg/day for 12 weeks), we studied the behavioral, cardiovascular, and neurochemical effects of abrupt clonidine withdrawal in seven patients with Tourette's syndrome aged 9 to 13 years. Five patients showed marked worsening of tics. After reinitiation of clonidine therapy, the time required for patients to return to prewithdrawal levels of tic symptoms ranged from two weeks to four months. Increases in motor restlessness, blood pressure, and pulse rate were also observed over the 72-hour period following abrupt withdrawal of clonidine. Plasma levels of free 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and urinary excretion of norepinephrine and epinephrine increased during the withdrawal period. Clonidine's effectiveness in Tourette's syndrome may be dependent on changes in dopaminergic as well as adrenergic mechanisms.

Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship.

Previous studies have suggested that obsessive-compulsive symptoms frequently occur among patients with Gilles de la Tourette's syndrome (TS). To examine the relationship between TS and obsessive-compulsive disorder (OCD), data from all first-degree relatives of TS probands were obtained with a semistructured interview designed to collect information on the presence of TS, other tic disorders, and neuropsychiatric illnesses during the lifetime of the individual. The rate of OCD among first-degree relatives was significantly increased over estimates from the general population and a control sample of adoptive relatives. The rates of TS, OCD, and chronic multiple tics (CMT) were virtually the same in families of probands with OCD (TS +/- OCD) when compared with families of probands without OCD (TS - OCD). Finally, the frequency of OCD without TS or CMT among first-degree relatives was significantly elevated in families of both TS + OCD and TS - OCD probands, suggesting that some forms of OCD may represent an alternative expression of the factors responsible for TS and/or CMT.

A twin study of Tourette syndrome.

In 43 pairs of same-sex twins, in which at least one co-twin had Tourette syndrome (TS), 30 pairs were probably monozygotic (MZ) and 13 were probably dizygotic (DZ). Concordances for TS were 53% and 8% for MZ and DZ pairs, respectively. When diagnostic criteria were broadened to include any tics in co-twins, concordance rates were 77% and 23% for MZ and DZ pairs, respectively. These concordances are consistent with genetic etiology. However, the fact that only 53% of MZ twins were fully concordant indicates nongenetic factors affect expression of TS. Presence of tics in discordant co-twins and timing of onset in partially concordant co-twins support an association between TS and tics in families with TS present. The data are inconclusive on whether some MZ twins with discordant co-twins are etiologically different from those who are concordant.

Clonidine treatment of Gilles de la Tourette's syndrome.

The safety and effectiveness of clonidine hydrochloride (3 to 5 micrograms/kg per day) were evaluated in 47 subjects with Gilles de la Tourette's syndrome, aged 7 to 48 years. Twenty-four subjects were randomly assigned to clonidine treatment and 23 to placebo. Forty subjects (21 given clonidine and 19 placebo) successfully completed the 12-week, double-blind clinical trial. Clinical ratings of tic severity improved for both groups. The magnitude of response was greater in the group receiving clonidine. Clinician-rated measures of motor tic severity, the degree to which the tics are "noticeable to others," motor tic counts from videotaped interviews, and parent-rated measures of impulsivity and hyperactivity were the most responsive to clonidine treatment. These results indicate that clonidine is more effective than placebo in reducing some of the tic and other behavioral symptoms associated with Gilles de la Tourette's syndrome.

Familial transmission of depression and alcoholism.

The familial transmission of major depression and alcoholism among probands who had depression and alcoholism was examined. Our findings indicated that depressives without alcoholism did not transmit alcoholism, and probands with depression and alcoholism tended to transmit both depression and alcoholism. This confirms the observation that depression and alcoholism are not manifestations of the same underlying disorder. An increased risk of anxiety disorders in the relatives of probands with alcoholism, which could specifically be attributed to the presence of alcoholism in addition to an anxiety disorder in the proband, was also observed. This suggested that the alcoholism in these probands may result from self-medication of anxiety symptoms. The results of this study underscore the importance of examining combinations of diagnoses in patients in decreasing the heterogeneity of diagnostic categories.

New data do not suggest linkage between the Xg blood group and bipolar illness.

The Xg blood group antigen (a genetic marker of a region of the X chromosome at a considerable distance from protan/deutan color blindness) was studied for linkage to bipolar manic-depressive illness. A multigenerational analytic method, taking variable penetrance into account, was used. In our series of six informative pedigrees, very close linkage could be definitively ruled out, and the likelihood of less tight linkage was consistently less than the likelihood of nonlinkage.

Panic disorder and major depression. Increased risk of depression, alcoholism, panic, and phobic disorders in families of depressed probands with panic disorder.

In a large, case-control family study of depression, 77 (58%) of 133 depressed probands displayed anxiety symptoms that met DSM-III criteria for agoraphobia, panic disorder, or generalized anxiety disorder. In two thirds of these 77 cases, these symptoms were associated with depressive episodes. In a previous study, the lifetime rate of major depression and anxiety disorders among first-degree family members of probands with major depression plus an anxiety disorder was found to be significantly increased regardless of when the anxiety symptoms occurred. In this study we analyzed our data according to the specific anxiety disorders observed. Major depression plus panic disorder in probands was associated with a marked increase in risk in relatives for a number of psychiatric disorders; relatives were more than twice as likely to have major depression, panic disorder, phobia, and/or alcoholism than the relatives of probands with major depression without any anxiety disorder. These results indicate that the relationship between major depression and anxiety disorders requires further study.

Subtypes of depression. Family study perspective.

To address the validity of subtype distinctions within a large family study of major depression, probands (N = 133) were classified into several non-mutually exclusive subcategories, including endogenous (n = 89), melancholic (n = 61), autonomous (n = 50), and delusional (n = 21). Age-corrected lifetime rates of depression and subtypes among first-degree relatives were then compared by the proband's depression subtype. Rates of major depression were highest for the relatives of probands with the autonomous and delusional subtypes, and while lower for the relatives of endogenous and melancholic probands, these rates were still higher than for the relatives of the remaining depressed probands or the relatives of normal controls. The depressed relatives of depressed probands with the endogenous, melancholic, autonomous, or delusional subtypes were more likely to have one of these subtypes than the depressed relatives of either the remaining depressed probands or the normal controls.

Onset of major depression in early adulthood. Increased familial loading and specificity.

In a family study of 133 probands with major depression and 82 normal control subjects, and 1,518 of their first-degree relatives, we found a substantial inverse relationship between the age of onset of major depression in the probands and the risk of major depression in their relatives. The relatives of probands whose onset of major depression occurred when they were younger than 20 years of age had the highest risk of major depression, compared with the relatives of probands who had later ages of onset or with the relatives of normal subjects. Probands with an age of onset of 40 years or more had familial loading that was only slightly higher than the families of normal control subjects. Our statistical methods enabled us to examine the relationship of the ages of onset in the probands and their relatives while accounting for possible confounding factors. More studies will be needed to sort out secular changes in the rates of the occurrence of major depression among young persons (cohort effect) from the high familial loading of major depression that has its onset in childhood and adolescence, and to determine whether the specificity of transmission of early-onset depression is the result of a single homogeneous disorder.

Appetite disturbance and excessive guilt in major depression. Use of family study data to define depressive subtypes.

A post hoc analysis of the relationship between depression in first-degree family members (N = 810) and specific patterns of "endogenous" symptoms in 133 probands with nonbipolar major depression revealed that concomitant appetite disturbance and excessive guilt in the depressed probands was associated with increased rates of major depression among family members. The depressed, interviewed relatives of depressed probands with appetite disturbance and excessive guilt were found to be at a 2.5 greater risk for this same subtype compared with the depressed, interviewed relatives of the remaining depressed probands. These findings suggest that this subtype of depression may "breed true" within these families.

Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment.

Stimulation of presynaptic alpha 2-adrenergic receptors located on norepinephrine (NE)-containing cells in the brain decreases the firing rate and turnover of NE in these neurons. To assess whether abnormalities in the regulation of the NE system during desipramine hydrochloride treatment may be present in depressed patients, the effects of an alpha 2-agonist, clonidine hydrochloride, on plasma levels of the NE metabolite 3-methoxy-4-hydroxy/phenethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in ten depressed patients before and during long-term desipramine treatment. Long-term desipramine treatment significantly attenuated the effects of clonidine on plasma MHPG level and BP, indicating that during desipramine treatment alpha 2-adrenergic receptors had become subsensitive. In addition, plasma MHPG levels were significantly reduced during long-term desipramine treatment. These findings are discussed in relation to the hypothesized therapeutic mechanism of action of desipramine and the hypotheses relating noradrenergic function and depression.