Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Striatal dopaminergic alterations in Tourette's syndrome: a meta-analysis based on 16 PET and SPECT neuroimaging studies.

Despite intense research, the underlying mechanisms and the etiology of Tourette's syndrome (TS) remain unknown. Data from molecular imaging studies targeting the dopamine system in Tourette patients are inconclusive. For a better understanding of the striatal dopamine function in adult dopamine-antagonist-free patients we performed a systematic review in August 2017 identifying 49 PET and SPECT studies on the topic of TS. A total of 8 studies appraised the dopamine transporter (DAT) with 111 Tourette patients and 93 healthy controls, and could be included in a meta-analytic approach. We found a significantly increased striatal DAT binding in Tourette patients (Hedges' g = 0.49; 95% CI: (0.01-0.98)), although this effect did not remain significant after correcting for age differences between cohorts. A second meta-analysis was performed for the striatal dopamine receptor including 8 studies with a total of 72 Tourette patients and 71 controls. This analysis revealed a nonsignificant trend toward lower dopamine 2/3 receptor binding in striatum of Tourette patients. Other analyses regarding study population characteristics in both the DAT and receptor meta-analysis did not show any meaningful results. Our results indicate that dopaminergic alterations in TS are likely and thereby this data would be in line with the current pathophysiological hypotheses of a dysfunction in the dopamine system, e.g., the hypothesis of tonic-phasic dysfunction. However, these analyses suffer from low effect sizes probably due to the heterogeneity of TS and highlight the need for further large-scaled neuroimaging studies.

DiGeorge syndrome : Relevance of psychiatric symptoms in undiagnosed adult patients.

DiGeorge syndrome or 22q11.2 deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability, schizophrenia and attention-deficit/hyperactivity disorder. Usually, the diagnosis of DiGeorge syndrome is made in early childhood. This article reports on the late diagnosis of a patient with panic disorder and comorbid major depression at the age of 51. Since genetic testing was not available before the 1990s, there might be many over 40-year-old patients, who remained undiagnosed. Psychiatric symptoms exhibit distinctive developmental trajectories and many of these exhibit an increase in incidence during adulthood. Hence, undiagnosed adult DiGeorge patients might present in psychiatric services. As in this case, a correct diagnosis of DiGeorge syndrome in adults may help to improve treatment and outcome.

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases.

Ketamine, a rapid-acting antidepressant and anti-suicidal agent, is thought to increase brain monoamine levels by enhancing monoamine release or inhibiting presynaptic monoamine-reuptake. Here we present two female inpatients suffering from treatment-resistant depression with recurrent severe suicidal crises receiving a combination of intravenous S-ketamine and oral tranylcypromine, which is a well-known irreversible monoamine oxidase (MAO) inhibitor. Since inhibition of monoamine-reuptake with concurrent blockade of MAO might trigger sympathomimetic crisis, this combination is considered hazardous. Nonetheless, cardiovascular parameters remained stable in both patients, while good anti-suicidal effects were observed. Hence, we put serious doubt on whether monoamine-reuptake inhibition is a relevant pharmacological effect of ketamine in humans.

Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Sequence analysis of the complete SLITRK1 gene in Austrian patients with Tourette's disorder.

Mutations in the gene SLITRK1 (Slit and Trk-like 1) have been reported in patients with Tourette's disorder (TD). We sequenced the entire SLITRK1 gene including the coding region the 5' and 3' untranslated region in 92 Austrian patients with TD. No nucleotide changes within the protein-coding region were identified. One patient was found to carry a variant within the 3' untranslated region (3383g>a), which was absent in 192 control individuals and which segregated in two additional family members with tic symptoms. In conclusion, our results provide no evidence for SLITRK1 playing a major role in TD.

Tourette's syndrome is not associated with interleukin-10 receptor 1 variants on chromosome 11q23.3.

Interleukin-10 receptor 1 (IL-10R1) single nucleotide polymorphisms, located on chromosome 11q23 - a strong candidate for linkage with Tourette's syndrome (TS) - have been investigated for association with TS. DNA of 77 patients with a DSM-IV (Diagnostic and Statistical Manual IV) diagnosis of TS and 250 healthy controls was genotyped. IL-10R1 was not associated with TS.

Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome.

We recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In the present study we sought to identify genetic variation in IMMP2L, which, through alteration of protein function or level of expression might contribute to the manifestation of GTS. We screened 39 GTS patients, and, due to the localization of IMMP2L in the critical region for the autistic disorder (AD) locus on chromosome 7q (AUTS1), 95 multiplex AD families; however, no coding mutations were found in either GTS or AD patients. In addition, no parental-specific expression of IMMP2L was detected in somatic cell hybrids containing human chromosome 7 and human cell lines carrying a maternal uniparental disomy for chromosome 7 (mUPD7). Despite the fact that no deleterious mutations in IMMPL2 (other than the inverted duplication identified previously) were identified in either GTS or AD, this gene cannot be excluded as a possible rare cause of either disorder.

Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report.

The usefulness of deep brain stimulation (DBS) of thalamic nuclei in Gilles de la Tourette syndrome (GTS) has recently been advocated. We report on a 14-month follow-up study of a patient with intractable GTS in whom bilateral DBS of the internal globus pallidus was carried out. Tic frequency per minute decreased by 73% in the postoperative phase and in particular the vocal tics became less intense. Pronation/ supination bradykinesia of the left extremities was a well-tolerated, permanent side effect. Pallidal DBS could become a valuable rescue therapy for otherwise intractable GTS.

Clonazepam in the long-term treatment of patients with unipolar depression, bipolar and schizoaffective disorder.

The value of a long-term treatment with clonazepam in the prophylaxis of affective disorder is discussed controversially in the scientific literature. Altogether there are only a few reports on the use of this compound as a mood stabilizer, most of them describing patients suffering from bipolar affective disorder. The aim of this investigation was to evaluate clonazepam as a phase prophylactic medication in affective disorder. We conducted a retrospective chart review in 34 out-patients of our lithium clinic (15 suffering from unipolar depression, 15 from bipolar disorder, four from schizoaffective disorder), who had been treated with clonazepam as a long-term medication. Clonazepam was either given as monotherapy, or as in the case of lithium non-responders, as adjunctive therapy. Patients with unipolar depression had significantly (P=0.026) less depressive episodes after initiation of treatment with clonazepam. Patients with bipolar disorder did not benefit from this therapy. Neither manic/hypomanic phases nor depressive episodes were reduced in this group of patients. Interestingly, clonazepam also reduced affective phases in our four schizoaffective patients on a trend level. Our results indicate that patients with unipolar depression may benefit from a maintenance treatment with clonazepam. Due to methodological limitations our results need to be replicated in controlled double-blind randomized clinical trials.

Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology.

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naïve or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of 5-HT1A receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age- and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [123I] beta-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drug-naïve TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

A longitudinal view of triggers and thresholds of suicidal behavior in depression.

BACKGROUND: Recurrent brief depressive disorder (RBD) and major depressive disorder (MDD) share the same diagnostic picture of full-blown depression and are both associated with increased suicide attempt rates. However, longitudinal diagnostic shifts from RBD to MDD or vice versa, called "combined depression" (CD), have demonstrated a substantially higher risk of suicide attempts in epidemiologic and clinical studies. Following the stress-diathesis model of suicidal behavior, we compared possible triggers and thresholds for suicidal behavior among patients with RBD, MDD, and CD. RBD and MDD diagnoses were based on DSM-IV criteria. Furthermore, the goal of this study was to determine if impulsivity as an underlying factor could explain high suicide attempt rates in CD. METHOD: A structured clinical interview evaluating comorbid Axis I and II disorders and RBD and a battery of instruments assessing suicidal behavior were administered to 101 patients with RBD (N = 27), MDD (N = 33), or CD (N = 41). RESULTS: Patients with CD showed significantly higher (p < .05) scores on measures of suicidal behavior in comparison with RBD and MDD patients. Together with comorbid substance abuse and marital status, CD was among the highest-ranking risk factors for suicide attempts. Impulsivity was identified as a major underlying factor, predicting 80.7% of suicide attempts. CONCLUSION: CD seems to be an important clinical risk factor for the prediction of suicide attempts, similar to risk factors such as substance use disorders and borderline personality disorder. All of these factors share the same diathesis for increased impulsivity and suicidal ideation, which could explain comorbidity and suicidal behavior. The coexistence of a greater propensity for suicidal ideation and impulsivity in RBD might also explain why such patients are more prone to attempt suicide, even if they do not, in the case of RBD, meet the duration criteria for MDD.

Atypical antipsychotics in mood disorders.

Bipolar disorder is ranked as the sixth most important worldwide cause of disability. Current treatment is based chiefly on lithium and/or anticonvulsants, of which sodium valproate is the most widely used. A significant minority of patients fail to respond fully to current treatments, particularly those with mixed mania and/or rapid cycling. Many patients are unable to tolerate the side-effects of current therapy in the long term, and adverse effects may contribute to the high rate of noncompliance observed in bipolar disorder. The shortcomings of current treatments are reflected in poor outcomes: two-thirds of patients with bipolar disorder require hospitalization on more than one occasion; employment and social functioning are significantly lower than in control groups; 93% of carers suffer at least moderate distress; and 25-50% of patients are believed to attempt suicide at least once. Bipolar disorder shares some features with schizophrenia, and several atypical antipsychotics have demonstrated efficacy in bipolar disorder. Quetiapine has a particularly favourable tolerability profile, with placebo-level extrapyramidal symptoms and prolactin levels across the entire dose range combined with a neutral effect on weight during long-term use, and may be a valuable treatment option in acute mania and bipolar disorder.