Does SSRI augmentation with antidepressants that influence noradrenergic function resolve depression in obsessive-compulsive disorder?

BACKGROUND: Obsessive compulsive disorder (OCD) often coexists with major depressive disorder (MDD). Serotonergic antidepressant medications have emerged as the treatment of choice for both OCD and MDD. In the usual course of events, both the patient's OCD and depressive symptoms improve in parallel following initiation of serotonin reuptake inhibitor (SRI) treatment for OCD. However, such is not always the case. We report here on a series of ten patients whose OCD but not depression improved following a trial of SRI therapy. METHOD: Ten patients with OCD and comorbid MDD who experienced a worsening or exacerbation of depressive symptoms while being maintained on an adequate dose of SRI therapy were treated using a combination of SRIs and agents with effects on noradrenergic reuptake. Response to treatment was based on clinician-ratings of severity and improvement of OCD and MDD (CGI-S and CGI-I). RESULTS: Following augmentation, nine of the ten patients had a significant improvement/resolution of their MDD, with little further change in the severity of their OCD. LIMITATIONS: Inferences from the results of this study are limited by the lack of a control group, the small sample size, and the use of nonstandardized ratings as measures of symptom severity. CONCLUSIONS: These results are of practical significance to clinicians insofar as they suggest a possible guideline to clinicians treating depression in OCD with SSRIs without success.     

奥氮平强化5-羟色胺再摄取抑制剂治疗难治性强迫症

目的 研究难治性强迫症用5-羟色胺再摄入抑制剂合用奥氮平强化治疗的疗效及安全性.方法 对难治性强迫症36例,采用Yale-Brown强迫量表,汉密顿焦虑量表(HAMA)及副反应量表(TESS)评定疗效和不良反应.结果 5-羟色胺再摄入抑制剂合用奥氮平治疗难治性强迫症疗效好.结论 5-羟色胺再摄入抑制剂合用奥氮平治疗难治性强迫症安全有效,值得推广.     

Prenatal antidepressant exposures and gastrointestinal complaints in childhood: A gut–brain axis connection?

Selective serotonin/norepinephrine reuptake inhibitors (collectively, SRIs) are the most commonly prescribed antidepressant agents for the treatment of depression in pregnancy. SRIs affect maternal and placental serotonin signaling, which might impact fetal brain development. Alterations in serotonin signaling might also impact the developing gut–brain axis (GBA) via alterations in the fetal enteric nervous system (ENS). Emerging evidence suggests that gestational SRI exposure may be associated with offspring gastrointestinal problems. However, prospective human studies of the effects of fetal SRI exposure on the ENS and function are absent in the literature. In this paper we present data demonstrating significant associations between prenatal SRI exposure and children's gastrointestinal (GI) problems in two well-characterized, prospective cohorts of preschool and later childhood individuals. The results support the hypothesis that prenatal SRI exposure can increase the risk for childhood GI difficulties. Further research is warranted on the potential SRI-induced changes to the child gut including the role of the microbiome and the GBA in the development of GI problems.     

Pharmacotherapy of compulsive hoarding

Compulsive hoarding is a common and potentially disabling disorder. This article reviews studies of the effects of hoarding on response to serotonin reuptake inhibitor (SRI) medications in patients with obsessive-compulsive disorder (OCD), as well as recent studies of pharmacotherapy specifically for patients with the compulsive hoarding syndrome. Taken together, the results of these studies indicate that the "conventional wisdom" that compulsive hoarding does not respond well to SRI treatment is wrong. SRIs appear to be as effective for compulsive hoarders as for nonhoarding OCD patients. A case is presented of a compulsive hoarding patient who responded well to pharmacotherapy with a novel agent. Symptom improvement from pharmacotherapy of compulsive hoarding appears to be at least as great as that resulting from cognitive-behavioral therapy (CBT). However, the combination of pharmacotherapy and CBT for compulsive hoarding is likely more effective than either treatment alone.     

Depression in comorbid obsessive-compulsive disorder and posttraumatic stress disorder

Previous findings suggested a unique role that depression symptoms might play in the comorbid relationship between obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). However, the nature of this role remains unclear. Thus, the current study examined ways in which OCD and PTSD symptoms vary as a function of depression, as well as the mediating role of depression in the OCD-PTSD relationship, in 104 individuals seeking treatment for refractory OCD. Findings revealed that depressed individuals in the treatment-refractory OCD sample report higher levels of overall obsessing and greater severity of PTSD. In addition, depression appeared to mediate the relation between OCD and PTSD. Implications of findings are discussed.     

Paediatric outcomes following intrauterine exposure to serotonin reuptake inhibitors: a systematic review

The use of serotonine reuptake inhibitors (SRIs) is increasing among Danish pregnant women. This systematic review addresses the potential adverse effects on the foetus and child of maternal SRI medication. The literature indicates a slightly increased risk of cardiovascular malformations and persistent pulmonary hypertension of the new-born, while evidence regarding the risk of preterm labour, low birth weight, low Apgar score, prolonged QT interval and miscarriage is less clear. An estimated 20-30% of infants will have neonatal symptoms following intrauterine SRI exposure. The symptoms may be caused by SRI withdrawal, toxicity or their overlap, but symptom aetiology basically remains controversial. The infants may exhibit neurological, gastrointestinal, autonomic, endocrine or respiratory symptoms. Although the symptoms are self-limited, the families may be seriously affected. In general, studies do not address this important aspect. Evidence concerning long-term effects is surprisingly sparse and many studies have important methodological limitations. However, present evidence does not convincingly indicate detrimental long-term effects. Until sufficient safety studies have been carried out, SRI must be used with caution in pregnancy and every treatment of the pregnant woman should be thoroughly considered.     

Clinical features associated to refractory obsessive-compulsive disorder

Some patients with obsessive-compulsive disorder (OCD) exhibit an unsatisfactory reduction in symptom severity despite being treated with all the available therapeutic alternatives. The clinical variables associated with treatment-refractoriness in OCD are inconsistently described in the literature. METHODS: To investigate factors associated with treatment-refractoriness of patients with OCD, we conducted a case-control study, comparing 23 patients with treatment-refractory OCD to 26 patients with treatment-responding OCD. RESULTS: The factors associated with refractoriness of OCD were higher severity of symptoms since the onset of OCD (p<0.001), chronic course (p=0.003), lack of a partner (p=0.037), unemployment (p=0.025), low economic status (p=0.015), presence of obsessive-compulsive symptoms of sexual/religious content (p=0.043), and higher scores on family accommodation (p<0.001). Only the three latter variables remained significantly associated with treatment-refractoriness after regression analyses. Limitations: small sample size, the biases and drawbacks inherent to a case-control study, and the inclusion criteria used to define the study groups may have limited the generalisation of the results. CONCLUSION: A major strength of this study is the systematic and structured evaluation of a vast array of variables related to the clinical expression of OCD, including epigenetic factors and ratings derived from instruments evaluating family accommodation. The presence of sexual/religious symptoms, low economic status and high modification on family function due to OCD were independently associated with treatment-refractoriness. Future longitudinal studies are warranted to verify if these variables represent predictive factors of treatment non-response.     

Treatment of obsessive-compulsive disorder in patients who have comorbid major depression

Many patients who have obsessive-compulsive disorder (OCD) also meet criteria for additional diagnoses such as mood, anxiety, and personality disorders. The presence of severe depression, and major depressive disorder per se, impedes response to treatment for OCD that uses the best available treatments. In this article, the comorbidity data in OCD are reviewed, then the relationship between depression and OCD treatment outcome is reviewed. Next, the derivation and implementation of a treatment program specifically for depressed OCD patients are illustrated with a case example. The article closes with a discussion of implications and directions gleaned from this single case study.     

强迫症药物疗效与六个功能基因的分子遗传药理学研究

目的　探讨与5-羟色胺系统和多巴胺系统有关的6个基因(5-羟色胺2A受体基因、5-羟色胺转运体基因、多巴胺D2受体基因、多巴胺D4受体基因、儿茶酚胺氧位甲基转移酶基因、单胺氧化酶A基因)与强迫症药物疗效之间是否存在关联。方法　收集了113个强迫症核心家系,对强迫症患者给予5-羟色胺回吸收抑制剂治疗,采用Yale-Brown强迫量表在治疗8周前后进行评定,按Yale-Brown强迫量表评分分为有效组和无效组。采用限制性片段长度多态性和可变数串联重复序列多态性技术对有效组和无效组的强迫症家系在6个基因的7个位点上进行传递不平衡检测。结果　未发现6个基因与不同药效的强迫症家系之间存在关联,但发现有效组和无效组在5-羟色胺2A受体基因-1438G/A位点基因型频率存在差异,无效组有更多的纯合子(χ2=4.69,P=0.03)。结论　5-羟色胺2A受体基因可能和强迫症药物治疗效果有关。     

Do antipsychotics ameliorate or exacerbate Obsessive Compulsive Disorder symptoms? A systematic review

BACKGROUND: Paradoxically, some reports in the literature support the use of antipsychotics in the treatment of Obsessive Compulsive Disorder (OCD), while other reports suggest that antipsychotics can exacerbate OCD symptoms. To date, there is no published systematic review of the relationship between OCD symptoms and antipsychotic drugs. METHODS: A Medline and PsychInfo search (1980-2003) was conducted to collect published reports of the interactions between antipsychotics and OCD symptoms. RESULTS: In the treatment of refractory OCD, case series, open label trials and placebo-controlled trials were found suggesting efficacy of antipsychotic augmentation to ongoing antidepressant treatment. In the placebo-controlled trials with haloperidol, risperidone, olanzapine, and quetiapine, a significantly higher response rate (46-71%) was found for the antipsychotic groups, compared to no response for the placebo groups. Reports of exacerbation of OCD symptoms with the use of atypical antipsychotics were limited to individuals with a primary psychotic disorder. LIMITATIONS: Definition of response in most of these treatment studies was based on a modest reduction of OCD symptoms, and no studies were available on long-term efficacy. There were also no published reports that systematically evaluated the incidence of OCD symptoms associated with atypical antipsychotics. CONCLUSIONS: All antipsychotics mentioned above had short-term controlled evidence to support their use as augmenting agents in the treatment of refractory OCD. The suggested management of OCD induction/exacerbation due to atypical antipsychotics is to increase the dose of the atypical antipsychotic and/or add a selective serotonin reuptake inhibitor.     

Peer assessment of social reputation in community samples of disruptive and nondisruptive children: Utility of the revised class play mthod

Discusses pharmacological treatment of childhood obsessive-compulsive disorder (OCD), chronic and underrecognized psychiatric condition that affects up to 2% to 3% of children and adolescents. Research in OCD in children, including neuropharmacology, brain imaging, genetics, and clinical phenomenology, informs current views of OCD pathophysiology. Contemporary research supports the notion of a dysregulation in serotonin subsystems in the central nervous system, with target areas of dysfunction including basal ganglia and orbitofrontal cortex. Pharmacotherapy, along with cognitive-behavioral approaches, constitutes the indicated treatment for childhood OCD. Pharmacological treatment is best guided by a phenomenological understanding of the type of obsessions and compulsions, the intensity and frequency of their presentation with attention to behavioral reinforcements, and psychosocial factors that affect the course of the disease. Serotonin-enhancing agents, such as fluoxetine, fluvoxamine, paroxetine, and sertraline and citalopram (SSRIs) are first-line pharmacological agents, whereas refractory symptoms can be treated by augmentation with neuroleptics or other agents. Clomipramine is as effective as the SSRIs but its use may be accompanied by increased side effects. Genetic factors probably influence susceptibility to OCD as well as response to treatment, and the elucidation of these and other risk factors will be important elements in the future understanding and treatment of this disorder.     

Obsessive–compulsive disorder and gut microbiota dysregulation

Obsessive–compulsive disorder (OCD) is a debilitating disorder for which the cause is not known and treatment options are modestly beneficial. A hypothesis is presented wherein the root cause of OCD is proposed to be a dysfunction of the gut microbiome constituency resulting in a susceptibility to obsessional thinking. Both stress and antibiotics are proposed as mechanisms by which gut microbiota are altered preceding the onset of OCD symptomology. In this light, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) leading to episodic OCD is explained not by group A beta-hemolytic streptococcal infections, but rather by prophylactic antibiotics that are administered as treatment. Further, stressful life events known to trigger OCD, such as pregnancy, are recast to show the possibility of altering gut microbiota prior to onset of OCD symptoms. Suggested treatment for OCD would be the directed, specie-specific (re)introduction of beneficial bacteria modifying the gut microbiome, thereby ameliorating OCD symptoms. Special considerations should be contemplated when considering efficacy of treatment, particularly the unhealthy coping strategies often observed in patients with chronic OCD that may need addressing in conjunction with microbiome remediation.     

Association between serotonergic candidate genes and specific phenotypes of obsessive compulsive disorder

BACKGROUND: The successful use of serotonin reuptake inhibitors (SRIs) in obsessive-compulsive disorder (OCD) has led to the hypothesis that serotonin plays a pivotal role in the pathogenesis of OCD. The purpose of the present study was to investigate the role of the serotonin transporter (5-HTT) and serotonin 5-HT1B and 5-HT2A receptor genes in OCD. METHOD: The distribution of polymorphic variants was analyzed in 156 OCD cases and 134 control individuals by means of case-control association studies. Potential relevant OCD phenotypes founded on age of onset, positive family history for OCD, clinical subtypes, comorbidity and symptom severity were stratified according to 5-HTT, 5-HT1B and 5-HT2A genotypes. RESULTS: Patients did not show significant differences in genotype distribution and allele frequency for polymorphisms investigated relative to controls. However, taking in account OCD phenotypes, we found indication towards an association of the 5-HTTLPR S-allele with female OCD patients, and the 5-HT2A G-allele and GG genotype with patients with a positive family history of OCD and an early onset of disease. CONCLUSIONS: Our data yields interesting preliminary results as regards the genetic underpinnings of OCD phenotypes that warrant further discussion and investigation.     

Prevention of the serotonin reuptake inhibitor discontinuation syndrome

Prevention of the serotonin reuptake inhibitor discontinuation syndrome (SRIDS) is an important issue. The author suggests: (1) serotonin reuptake inhibitors (SRIs) should be used only when they are necessary. Sometimes tablets should be replaced with other treatment modalities; (2) patients should be given the lowest dosage of SRIs possible; (3) patients who have a history of medication noncompliance, who have experienced the discontinuation symptoms in the past, or who have treatment-emergent anxiety are at highest risk for experiencing the SRIDS and need closer monitoring; (4) SRIs should be tapered prior to stoppage; (5) generic drugs are allowed up to a 20% difference in bioequivalence from the brand original. Patients should receive continuity of supply from the dispenser, with no intermanufacturer switching; (6) patients and healthcare professionals should be educated to ensure that SRIs are not stopped abruptly; (7) neonatal SRIDS can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and physician should take this into consideration when making treatment decision.     

Osteochondritis dissecans of the knee; long-term clinical outcome following arthroscopic debridement

We reviewed 32 knees in 26 patients who had previously undergone arthroscopic debridement for symptomatic osteochondritis dissecans (OCD) of the knee. The patients were followed up at a minimum of 11 years following surgery and were evaluated clinically using the American Knee Society Clinical Rating Score. Additional evaluation was performed using the Hughston Scale to include radiographic assessment. The mean American Knee Society Score was 179 (out of 200), indicating good clinical function. Radiographically, however, only 29% scored excellent or good on the Hughston Scale. Younger patients with a small, stable (and therefore preserved), medial femoral condyle lesion had the best prognosis. Whilst more novel and complex options such as chondrocyte implantation are being assessed for the treatment of OCD, it is clear that within this study group careful debridement with removal of loose tissue can achieve good clinical results in the long term. There was however radiographic evidence of early degenerative joint disease in 17/24 (71%) of patients reviewed. Patients undergoing excision of OCD fragments did worse than those in whom the fragment was preserved, however the risk of further surgery is raised if a fragment is left in situ at initial surgery.     

Obsessive-compulsive symptom dimensions as predictors of compliance with and response to behaviour therapy: results from a controlled trial

BACKGROUND: Recent factor-analytic studies in obsessive-compulsive disorder (OCD) identified consistent symptom dimensions. Support for the validity of these dimensions comes from studies of psychiatric comorbidity, functional brain imaging, genetic transmission, and treatment response to medications. This study examined whether previously identified OCD symptom dimensions are associated with treatment compliance and response to behaviour therapy (BT) for OCD. METHODS: One hundred and fifty-three OCD outpatients who participated in a multi-centre randomised controlled trial of computer- versus clinician-guided BT for OCD were included in the study. Logistic and multiple regression models tested for significant predictors of compliance with and response to BT and relaxation. RESULTS: The patients studied were phenomenologically comparable (including the presence of 'pure' obsessions and mental rituals) to those in previous serotonin reuptake inhibitor (SRI) trials and those in clinical epidemiology studies. High scorers on the 'hoarding' dimension were more likely to drop out prematurely from the study and tended to improve less. For those completing treatment, the strongest predictor of outcome was pre-treatment severity. Initial depression scores were unrelated to outcome. After controlling for symptom severity, higher scores on the 'sexual/religious obsessions' factor predicted poorer outcome with BT, especially when computer-guided. CONCLUSIONS: BT is especially indicated for OCD patients with aggressive/checking, contamination/cleaning and symmetry/ordering symptoms. Previous accounts of unsuccessful BT in patients with hoarding symptoms may be due in part to their propensity to drop out earlier from treatment. Patients with sexual/religious obsessions, but not those with mental rituals, might respond less well to traditional BT techniques. Existing treatments need to be refined and/or new treatments developed to improve these patients' adherence and response to treatment.     

Effects of 5-azacytidine in Syrian golden hamsters: toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis.

5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F1D) hamsters wherein benzol[a]pyrene (BP) from sustained release implants (SRI) induces preneoplastic mucosal changes which progress to bronchogenic cancer. In pilot studies to evaluate AZC toxicity, a dose schedule of 5 mg/kg biweekly was found suitable and was then used for long-term administration in all subsequent studies. Three groups of outbred hamsters were studied: BP SRi alone (n = 60), BP SRI + AZC (n = 60), and AZC alone (n = 54). AZC treatment was begun 3-5 days after SRI placement. Sixty-one days after the start of the experiment, seven or eight hamsters were sacrificed from each group. Later sacrifices were at 3-week intervals in groups receiving BP SRI and at 6-week intervals in the AZC only group. Four groups of F1D syngeneic hamsters were studied: BP SRI alone (n = 50); BP + AZC starting 3-5 days after SRI placement and continuing until death (n = 52); BP + AZC from 3 to 5 days until 75 days after SRI placement (n = 49); BP + AZC starting 80 days after SRI placement and continuing until death (n = 52). Hamsters (n = 9-14) from each group were sacrificed at 120, 150, 180, and 220 days after SRI implantation. AZC alone was not carcinogenic under these conditions. Both outbred and F1D hamsters treated with early or continuous AZC had slower rates of neoplastic change from BP SRI than did animals receiving BP SRIs alone or BP + late AZC. The incidence of epidermoid cancer were the same for all regimens, but the tumors in those receiving AZC early in carcinogenesis were smaller than in those receiving late or no AZC. The incidences of nonepidermoid cancer were lower in those receiving AZC during early carcinogenesis, and larger tumors were noted in the absence of AZC. Thus, within the study period in this unique hamster lung cancer model, AZC given early in carcinogenesis inhibited only the later (promotional) phase of BP epidermoid carcinogenesis, but inhibited all phases of nonsquamous cancer development induced by BP. This differential modulation of bronchial carcinogenesis, which occurs from AZC given during preneoplastic stages, may prove useful for delineating molecular mechanisms underlying specific phenotypic types of bronchogenic cancers.     

Postpartum onset obsessive-compulsive disorder: diagnosis and management

Summary The postpartum period is associated with an increased risk of developing obsessive-compulsive disorder (OCD) in women. Postpartum onset OCD is often undiagnosed and untreated resulting in serious consequences for the patient, her family and the newborn. The symptoms of postpartum onset OCD may consist of obsessional intrusive thoughts about harming the newborn without compulsions or with both obsessions and compulsions. In this review, the phenomenology of postpartum onset OCD is described as well as strategies for screening and diagnosis. The review also characterizes the differences between postpartum onset OCD and postpartum depression and postpartum psychosis and explores strategies for managing postpartum onset OCD patients. Issues regarding pharmacologic treatment of OCD in breastfeeding mothers are also reviewed.     

Glutamatergic modulatory therapy for Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the presence of chronic, fluctuating motor and vocal (phonic) tics. The disorder is commonly associated with a variety of comorbidities including obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), school problems, anxiety, and depression. Therapeutically, if tics are causing psychosocial or physical problems, symptomatic medications are often prescribed, typically alpha-adrenergic agonists or dopamine antagonists. Recognizing that therapy is often ineffective and frequently associated with unacceptable side-effects, there is an ongoing effort to identify new tic-suppressing therapies. Several lines of evidence are presented that support the use of glutamate modulators in TS including glutamate’s major role in cortico-striatal-thalamo-cortical circuits (CSTC), the recognized extensive interaction between glutamate and dopamine systems, results of familial genetic studies, and data from neurochemical analyses of postmortem brain samples. Since insufficient data is available to determine whether TS is definitively associated with a hyper- or hypo-glutamatergic state, potential treatment options using either glutamate antagonists or agonists are reviewed. Data from studies using these agents in the treatment of OCD are presented. If validated, modulation of the glutamate system could provide a valuable new pharmacological approach in the treatment of tics associated with Tourette syndrome.