Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder.

Family studies suggest an interrelationship between Gilles de la Tourette Syndrome (GTS) and some forms of obsessive-compulsive disorder (OCD). Some authors consider GTS to be part of a serotonergically mediated cluster of OCD spectrum disorders. The present study was undertaken to compare measures of psychopathology, personality and blood serotonin between GTS and OCD (without tics), and to investigate whether an OCD spectrum hypothesis is supported for GTS. Fifteen GTS without OCD subjects, 21 tic with (+) OCD subjects, 15 OCD without tic subjects and 26 controls (all without serotonergic medication) were evaluated with self-rated and clinician-rated measures of psychopathology and personality. Whole blood serotonin (5-HT) and platelet monoamine oxidase activity (MAO) was measured, and Spearman's correlations were calculated between whole blood 5-HT, MAO and rating scale scores within the entire sample and within subgroups. There were main effects of OCD on anxiety, obsessive-compulsive, neuroticism and extraversion scores. There were main effects of tics on depression, obsessive-compulsive, trait anxiety and neuroticism scores, and on platelet MAO. There were interaction effects on platelet MAO, 5-HT, Yale-Brown Obsessive-Compulsive Rating Scale severity, trait anxiety and Eysenck Personality Questionnaire neuroticism scores. Platelet MAO activity was elevated in tic-free OCD subjects when compared to tic + OCD, GTS without OCD and controls. Whole blood 5-HT was lowered in tic + OCD patients in comparison to GTS without OCD and tic-free OCD subjects. Whole blood 5-HT and obsessive-compulsive severity were negatively correlated within OCD without tic patients and MAO and Leyton Obsessive Inventory scores were negatively related within GTS without OCD patients. The biochemical data of this study suggest that in tic + OCD and in tic-free OCD patients, 5-HT dysregulations play a role, but not necessarily in pure GTS. Serotonergic dysregulations within tic + OCD and tic-free OCD patients are distinct, suggesting differences in underlying pathophysiology. The finding that obsessions and compulsions can be associated with either 5-HT hypofunctionality or hyperfunctionality reveals a major weakness in the OCD spectrum theory, i.e. that the associations between obsessive-compulsive behaviours and 5-HT abnormalities are less specific than suggested by the original obsessive-compulsive spectrum model.     

Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D_2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge.Changes in [¹¹C]raclopride binding potential (BP_ND) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg^?1) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D_2/3 receptor BP_ND and change in BP_ND following amphetamine as a measure of dopamine release.Voxel-based analysis revealed significantly decreased baseline [¹¹C]raclopride BP_ND in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP_ND following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP_ND changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP_ND.This study provides evidence for decreased striatal D_2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.     

Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS)

There is evidence that motor and premotor cortex are hyperexcitable in obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). We tested whether low-frequency repetitive transcranial magnetic stimulation (rTMS) could normalize overactive motor cortical regions and thereby improve symptoms. Subjects with OCD or TS were treated with active rTMS to the supplementary motor area (SMA) for 10 daily sessions at 1 Hz, 100% of motor threshold, 1200 stimuli/day. Suggestions of clinical improvement were apparent as early as the first week of rTMS. At the second week of treatment, statistically significant reductions were seen in the YBOCS, YGTSS, CGI, HARS, HDRS, SAD, BDI, SCL-90, and SASS. Symptoms improvement was correlated with a significant increase of the right resting motor threshold and was stable at 3 months follow-up. Slow rTMS to SMA resulted in a significant clinical improvement and a normalization of the right hemisphere hyperexcitability, thereby restoring hemispheric symmetry in motor threshold.     

Gender in obsessive-compulsive disorder: clinical and genetic findings.

BACKGROUND: There is increasing recognition that obsessive-compulsive disorder (OCD) is not a homogeneous entity. It has been suggested that gender may contribute to the clinical and biological heterogeneity of OCD. METHODS: Two hundred and twenty patients (n=220; 107 male, 113 female) with DSM-IV OCD (age: 36.40+/-13.46) underwent structured interviews. A subset of Caucasian subjects (n=178), including subjects from the genetically homogeneous Afrikaner population (n=81), and of matched control subjects (n=161), was genotyped for polymorphisms in genes involved in monoamine function. Clinical and genetic data were statistically analyzed across gender. RESULTS: Compared with females, males with OCD (1) had an earlier age of onset, and a trend toward having more tics and worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis I comorbidity, and (3) in the Caucasian group, were more likely to have the high activity T allele of the EcoRV variant of the monoamine oxidase A (MAO-A) gene compared to controls, and (4) in the Afrikaner subgroup, were more frequently homozygous for the C allele at the G861C variant of the 5HT(1D beta) gene than controls. Females with OCD (1) reported more sexual abuse during childhood than males, (2) often noted changes in obsessive-compulsive symptoms in the premenstrual/menstrual period as well as during/shortly after pregnancy, and with menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for the low activity C allele of the EcoRV variant of the MAO-A gene compared to controls, with this allele also more frequent in female patients than controls. CONCLUSION: This study supports the hypothesis that gender contributes to the clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of genetic susceptibility to OCD may be present. Further work is, however, needed to delineate the mechanisms that are responsible for mediating the effects of gender.     

The relationship of plasma clomipramine and N-desmethylclomipramine to response in obsessive-compulsive disorder

The clinical significance of the effects of pharmacotherapy and the relationship between plasma tricyclic concentrations and outcome in 33 obsessive-compulsive disorder (OCD) patients who completed 10 weeks of treatment with clomipramine (239.4 +/- 57.0 mg/day) were analyzed. Results revealed that at the end of treatment, OCD symptoms had decreased to a subclinical level in 15 (47%) patients and that nearly 33 percent of the sample was virtually symptom free. However, 1 out of 4 patients failed to improve. Analysis of plasma levels (clomipramine 169.9 +/- 102.1 ng/ml; N-desmethylclomipramine 379.0 +/- 160.6 ng/ml) revealed that responders had significantly higher clomipramine levels and a trend toward lower desmethylclomipramine/clomipramine ratios. A significant degree of correlation was also obtained between plasma levels of clomipramine, but not N-desmethylclomipramine, and post-treatment outcome measures.     

儿茶酚氧位甲基转移酶基因多态性与单纯强迫症及共病双相障碍强迫症的关联分析

目的 探讨中国汉族人群中儿茶酚氧位甲基转移酶(COMT)基因多态性与单纯强迫症以及共病双相障碍强迫症之间的关系.方法 按美国《精神疾病诊断与统计手册》(DSM-Ⅳ),对符合诊断标准的单纯强迫症患者(单纯强迫症组)86例、共病双相障碍的强迫症患者(共病组)76例和正常对照(正常对照组)120例分别应用聚合酶链式反应(PCR)及限制性片段长度多态性(RFLP)技术检测COMT基因的多态性,采用病例-对照的关联分析方法对3组基因型和等位基因频率进行分析.结果 3组COMT基因型符合Hardy-Weinberg平衡法则;COMT的基因型和等位基因频率分布在3组间差异无统计学意义(P＞0.05);经性别分层后,3组中COMT基因型与等位基因频率的分布差异也无统计学意义(P＞0.05).结论 COMT基因多态性与单纯强迫症及共病双相障碍的强迫症可能无关联.     

The importance of nicotinic acetylcholine receptors in schizophrenia,bipolar disorder and Tourette's syndrome

As the prevalence of tobacco use has decreased, it has become clear that individuals with mental illness comprise a substantial portion of the remaining smokers. Seventy to eighty percent of patients with schizophrenia smoke and their smoking is established before their first psychotic episodes or the initiation of treatment. Many patients with schizophrenia, and approximately 50% of their first degree relatives have abnormalities in auditory sensory gating and/or smooth pursuit eye movements. These abnormalities are corrected by nicotine, and they appear to be transmitted as autosomal dominant traits. Evidence is accumulating that these abnormalities reflect genetic variations in nicotine receptor number and function, that may increase susceptibility for schizophrenia. Recent studies suggest that bupropion, added to treatment with an atypical antipsychotic, can enhance the likelihood of smoking cessation or reduction in patients with schizophrenia. The prevalence of smoking is also substantially increased among patients with bipolar disorder, perhaps especially so among those with psychotic features. Nicotine delivered by gum or transdermal patch can provide short term relief for exacerbations of Tourette's Syndrome, but its use is limited by frequent toxicity, primarily nausea.     

A possible relationship between catecholamines and acute toxicity of desipramine

Summary Acute toxicity of desipramine in mice was shown to be influenced by other drugs. Pretreatment with reserpine but not with chlorpromazine, disulfiram, or p-chlorophenylalanine protected mice against desipramine toxicity. Reserpine protection was reversed by dopa or dopa and disulfiram but not by methyldopa or 5-hydroxytryptophan. These results suggested a relationship between catecholamines and desipramine toxicity.     

MTHFR基因多态性与唐氏综合征发生易感性的研究

目的通过相关人群的基因型分析,了解5,10-亚甲基四氢叶酸还原酶（methylenetetrahydmfolate reductase,MTHFR）基因突变（677C→T）同广东人群生育唐氏综合征的相关性。方法采用PCR—RFLP方法对35例生育过DS患儿的母亲以及75例从未生育过DS患儿的母亲进行基因型分析,通过比较突变基因的分布频率的差异程度,判断突变基因情况同生育唐氏综合征的相关度。结果在35例阳性病例中,出现突变的8例,其中TT、基因型为5例,Tc型为3例;75例对照组病例中,出现突变的为6例,其中TT基因型为2例,TC型为4例。结论通过广东人群的相关性研究表明其MTHFR基因的677C-T突变,同生育唐氏综合征存在相关,应加强阳性人群的监控。     

A controlled study of fluvoxamine and exposure in obsessive-compulsive disorder

DSM-3 obsessive-compulsive out-patients were randomly assigned to fluvoxamine with antiexposure (F), fluvoxamine with exposure (Fe), or placebo with exposure (Pe) for 24 weeks. Of 65 patients offered treatment 60 entered the trial, 50 reached week 8, 44 completed treatment to week 24, and 37 reached follow up to week 48. On average the patient had depressed mood (mean Hamilton depression rating scale = 19). Drop-out numbers, clinical status and behavioural measures were comparable across groups. Most F patients did not do antiexposure, but Fe and Pe patients complied in doing exposure. All three groups improved in rituals and depression from week 0 to week 24 and 48, with a slight but non-significant superiority for combined treatment up to week 24. At week 8 there was a drug between-group effect on rituals, but not on depression. At week 24 there was a drug between-group effect on depression, but not on rituals. The drug superiority was short-lived. At week 48 there was no between-group difference in rituals or depression. Depression was related to ritual outcome at week 24 in F, and tended to be so in Fe.     

Treatment strategies of obsessive-compulsive disorder and panic disorder/agoraphobia

Anxiety disorders represent the most prevalent psychiatric disorders. In addition, a considerable burden is associated with them, not only for individual sufferers, but also for the health care system. However, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of recommendations for the pharmacological treatment of two common anxiety disorders, in particular obsessive-compulsive disorder (OCD) and panic disorder (PD). The first-line treatments of OCD include medium-high doses of selective serotonin reuptake inhibitors (SSRIs) and clomipramine, a tricyclic (TCA) antidepressant with prevalent serotonergic activity. The recommended drugs for PD include SSRIs, TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs); in treatment-resistant cases, benzodiazepines like alprazolam may be used in patients with no history of addiction and tolerance. Other treatment options include irreversible and reversible monoamine-oxidase inhibitors, hydroxyzine, and others. Besides pharmacological treatments, some psychological strategies have been shown to be effective, in particular, cognitive behavior therapy (CBT) and other variants of behavior therapy that have been sufficiently investigated in controlled studies, and, therefore, will be reviewed herein.     

Management of tics and Tourette's disorder: an update

Importance of the field: Tic disorders are fairly prevalent neuropsychiatric disorders. While a proportion of children may not present to the clinician's office for management of tic disorders, another proportion may present with severe symptoms that impair social and occupational functioning. A combination of psychosocial interventions and pharmacological approaches are required in these cases. While alpha-2 agonists and dopamine antagonists constitute the mainstay of pharmacological agents for tic disorders, advances in neurobiology and psychopharmacology have discovered newer avenues for treatment of tic disorders.

Areas covered in this review: Apart from reviewing evidence based literature and recent updates on alpha-2 agonists and dopamine antagonists in treating tic disorders, the review also includes novel treatment approaches such as glutamate modulators, nicotinic agents, antiandrogens and botulinum injection. In addition, a brief overview of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS) and habit reversal training is also provided.

What the reader will gain: A clear and concise review of the therapeutic options and advances in management of tic disorders.

Take home message: In addition to psychosocial interventions, alpha-2 agonists and dopamine antagonists constitute the mainstay of treatment approaches for treating tic disorders. Additional treatment options such as ropinirole, pramipexole and tetrabenazine may be useful if patients do not respond to the primary agents. Severe intractable cases might need a referral to specialist centers to consider the possibility of using ECT, TMS or DBS.     

A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder

SUMMARY: While the usefulness of clomipramine and selective serotonin reuptake inhibitors (SSRIs) in obsessive-compulsive disorder (OCD) has been established, the efficacy of serotonin-norepinephrine reuptake inhibitors remains to be determined. This report describes the first randomized double-blind comparison study of an SNRI in patients with obsessive-compulsive disorder. The current study compares the efficacy and tolerability of venlafaxine with paroxetine. One hundred and fifty patients with primary OCD according to DSM-IV criteria were randomly assigned in a 12-week double-blind trial to receive dosages titrated upward to 300 mg/d of venlafaxine (n = 75) or 60 mg/d of paroxetine (n = 75). Primary efficacy was assessed by the change from baseline on the Yale-Brown obsessive-compulsive scale (Y-BOCS). Other assessments throughout the trial included the Hamilton depression rating scale, and the Hamilton anxiety rating scale. An intent-to-treat, last-observation-carried-forward analysis demonstrated a mean decrease on the Y-BOCS of 7.2 +/- 7.5 in the venlafaxine group and of 7.8 +/- 5.4 in the paroxetine group. In both treatment groups, a responder rate (decrease > 35% on the Y-BOCS) of approximately 40% was found. There were no significant differences between venlafaxine and paroxetine with regard to response or responder rates. The incidence of adverse events for venlafaxine and paroxetine was comparable. The most common side effects for venlafaxine were somnolence, insomnia, a dry mouth, and sweating; and for paroxetine somnolence, sweating, nausea, and headache. These results show that venlafaxine was equally effective to paroxetine in treating patients with OCD. Venlafaxine may be a useful therapy for obsessive-compulsive patients, but is not superior to SSRIs.