Sustained response versus relapse: the pharmacotherapeutic goal for obsessive-compulsive disorder

Convincing evidence from placebo-referenced randomized controlled trials supports efficacy for clomipramine and selective serotonin reuptake inhibitors for acute treatment of obsessive-compulsive disorder. It remains less conclusively understood whether these agents maintain efficacy over the longer term. This paper systematically reviews long-term medication studies in obsessive-compulsive disorder. Studies of clomipramine, fluoxetine and sertraline investigated 'responders' from acute treatment trials and extended treatment up to 12 months versus placebo. Responses to medication were sustained. A 24-week placebo-controlled trial of escitalopram (10 mg or 20 mg/day) and paroxetine (40 mg/day) demonstrated ongoing efficacy for all three treatments. Studies that randomized treated cases to placebo demonstrated reemergence of symptoms in the placebo-treated cohort. Six relapse prevention trials were found by systematic search. Some, but not all, revealed significant advantages for remaining on medication. Paroxetine (20-60 mg/day) and escitalopram (10 or 20 mg/day) were each found to outperform placebo in preventing relapse during 24 weeks of double-blind, randomized follow-up. Meta-analysis, using Review Manager software (4.2.8), detected overall superiority of selective serotonin reuptake inhibitors to placebo in preventing relapse among adult treatment-responders. Worsening by five Yale-Brown Obsessive Compulsive Scale points emerged from the review as a suggested threshold for relapse. Viewed collectively, these results suggest that selective serotonin reuptake inhibitors are effective long-term treatments and relapse prevention represents the treatment target for obsessive-compulsive disorder.     

Orbitofrontal cortex dysfunction in obsessive-compulsive disorder? II. Olfactory quality discrimination in obsessive-compulsive disorder.

BACKGROUND: Olfactory quality discrimination is a putative marker of orbitofrontal cortex function in mammals. As this portion of the cerebral cortex was repeatedly implicated in the pathophysiology of obsessive-compulsive disorder (OCD) this study was designed in an attempt to quantify this behavioural function in OCD patients. METHODS AND RESULTS: Olfactory quality discrimination was compared in OCD patients and healthy controls. Thirty two subjects participated in the study: 16 (13 women and 3 men) medication free OCD outpatients and 16 sex and age matched healthy controls. Olfactory tests consisted of determination of detection thresholds to isoamyl acetate, and a three way forced choice quality discrimination task, using isoamyl acetate, citral and eugenol as stimuli. No significant differences in sensitivity and performance of the quality discrimination task between the two groups were found. Within the OCD group the more severely affected patients (Y-BOCS>29) performed significantly better than the less severely affected (Y-BOCS<30) patients on the more difficult part of the quality discrimination task. Within this subgroup of patients the correlation between performance on the olfactory task and a previously reported alternation task tended to be negative as compared to a significantly positive correlation in the control group. CONCLUSIONS: It seems that olfactory quality discrimination may prove to be a useful noninvasive marker of prefrontal cortex function in OCD. Furthermore, the organization of functional modules within the orbitofrontal cortex, rather than a simple dysfunction, may prove to characterize OCD.     

Pharmacotherapy of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a potentially devastating illness, both to the patient and family members. Its etiology is unclear, but some evidence points toward dysfunction in an orbitofrontal striatal-limbic neuronal loop. Although many agents have been used, clomipramine, a tricyclic antidepressant, appears to be the most promising therapy. Clomipramine was approved by the Food and Drug Administration and released for general use in early 1990 under the brand name Anafranil. Clomipramine's adverse effect profile is similar to that of currently marketed tricyclic antidepressants; however, it is associated with a higher frequency of seizures, estimated to be 0.7%. Although other serotonergic agents such as fluoxetine have shown promise in OCD, they have been studied only in a limited number of patients. Other agents, with the possible exception of monoamine oxidase inhibitors, either have resulted in inconsistent improvement or have been reported in an anecdotal fashion.     

D-Amphetamine in obsessive-compulsive disorder

In a double-blind crossover study, single doses of d-amphetamine and placebo were administered to 12 patients with severe chronic obsessive-compulsive disorder (OCD). Improvement of obsessional symptoms was significant on clinical ratings and was correlated with improved performance on an attention task. Changes were also significant for self-rated measures of activation and altered reality. The behavior response to amphetamine was not statistically correlated with subsequent improvement during a 6-week clomipramine trial, although the direction of change was the same during both treatments for every patient studied.     

Acute psychostimulant challenge in primary obsessive-compulsive disorder.

The effects of acute oral administration of methylphenidate 40 mg versus dextroamphetamine 30 mg versus matched placebo were compared in 11 patients with primary obsessive-compulsive disorder. Dextroamphetamine but not methylphenidate had a significantly greater antiobsessive-compulsive effect as measured by the Comprehensive Psychiatric Rating Scale--Obsessive-Compulsive Subscale, as compared with placebo. This effect appeared unrelated to their effect on depression although a differential effect of the two psychostimulants on anxiety was observed. Although both these stimulants affect serotonin, the differences noted between dextroamphetamine and methylphenidate suggest that catecholamines may be implicated in the pathophysiology of obsessive-compulsive disorder.     

Evidence-based pharmacotherapy of obsessive-compulsive disorder

Pharmacological strategies for the treatment of obsessive-compulsive disorder (OCD) continue to develop apace but deficiencies remain. We present an updated literature review of the evidence supporting available strategies. We aim to answer key questions including: (1) What are the first-line treatments? (2) Does pharmacotherapy improve health-related quality of life? (3) How do we evaluate clinical response and relapse? (4) How long should treatment continue? (5) Can we predict treatment outcomes? (6) What is the management of treatment-refractory OCD? Selective serotonin reuptake inhibitors (SSRIs) remain the pharmacological treatment of choice for most patients and are associated with improved health-related quality of life. However, discontinuation is associated with relapse and loss of quality of life, implying treatment should continue long term. A substantial minority of patients fail to respond to SSRI. Such patients may respond to strategies such as dose elevation or adjunctive antipsychotic, although long-term trials validating the effectiveness and tolerability of these strategies are relatively lacking. Newer compounds targeting other neurotransmitter systems, such as glutamate, are undergoing evaluation.     

Drug treatment of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is an uncommon but difficult to manage problem. Behaviour therapy is the treatment of choice, with clomipramine as an adjunct in patients with coexisting depression. However, the incidence of side effects with the doses required (up to 200 mg daily, or occasionally higher) is high, and the side effects may be intolerable to some patients. Benzodiazepines have no effect on the core symptoms of OCD, and their usefulness as long term anxiolytics is outweighed by the risks of physical and psychological dependence. There is no place for antipsychotic drugs in managing obsessive-compulsive disorder.     

Evidence-based pharmacotherapy of obsessive-compulsive disorder

Obsessive-compulsive disorder is a prevalent and disabling lifespan disorder. Clomipramine and the SSRIs have been found to be effective across the range of symptoms, both in acute and longer-term studies. Meta-analyses have reported a larger treatment effect for clomipramine relative to the SSRIs, but this is not supported by evidence from head-to-head comparator studies and, based on their superior safety and tolerability, SSRIs are the preferred option for long-term treatment in most cases. The treatment-effect is usually gradual and partial, and many patients fail to respond adequately to first-line treatment. Pharmacological options for refractory cases include switching SRI, increasing the dose, or augmenting with an antipsychotic agent. Novel strategies are under investigation for this highly morbid group. This paper reviews the key questions related to OCD pharmacotherapy, synthesizing evidence derived from randomized controlled trials, meta-analyses and consensus guidelines.     

Fluoxetine treatment of obsessive-compulsive disorder

Fluoxetine hydrochloride, a new antidepressant, was administered to 10 obsessive-compulsive patients, and the effects of treatment were examined in a single-blind placebo design. The effects of fluoxetine were examined with respect to depressive symptomatology and obsessions and compulsions per se. The results suggest that fluoxetine affected depressive symptoms but also had an effect on self-reported measures of obsessions and ritualistic behavior. Results are discussed in terms of improvement in obsessive-compulsive disorder, the relation of improvement to initial levels of depression, and patients' ability to tolerate the drug.     

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.     

Methylphenidate in primary obsessive-compulsive disorder

An acute methylphenidate challenge was performed on 13 patients with primary obsessive-compulsive disorder. There was no overall effect of methylphenidate on mood or obsessive-compulsive behavior. However, on various behavioral scales, four patients had an antiobsessive-compulsive response and one patient an antidepressant response to methylphenidate. The clinical and theoretical implications of these findings are discussed.     

Trajectory in obsessive-compulsive disorder comorbidities

The main goal of this study is to contribute to the understanding of the trajectory of comorbid disorders associated with obsessive-compulsive disorder (OCD) according to the first manifested psychiatric disorder and its impact in the clinical course of OCD and subsequent psychiatric comorbidities. One thousand and one OCD patients were evaluated at a single time point. Standardized instruments were used to determine the current and lifetime psychiatric diagnoses (Structured Clinical Interview for DSM-IV Axis I and for impulse-control disorders) as well as to establish current obsessive-compulsive, depressive and anxiety symptom severity (Yale-Brown Obsessive-Compulsive Scale; Dimensional Yale-Brown Obsessive-Compulsive Scale, Beck Depression and Anxiety Inventories and the OCD Natural History Questionnaire). To analyze the distribution of comorbidities according to age at onset Bayesian approach was used. Five hundred eight patients had the first OC symptom onset till the age of 10 years old. The first comorbidity to appear in the majority of the sample was separation anxiety disorder (17.5%, n=175), followed by ADHD (5.0%, n=50) and tic disorders (4.4%, n=44). OCD patients that presented with separation anxiety disorder as first diagnosis had higher lifetime frequency of post-traumatic stress disorder (p=0.003), higher scores in the Sexual/Religious dimension (p=0.04), Beck Anxiety (p<0.001) and Depression (p=0.005) Inventories. OCD patients that initially presented with ADHD had higher lifetime frequencies of substance abuse and dependence (p<0.001) and worsening OCD course (p=0.03). OCD patients that presented with tic disorders as first diagnosis had higher lifetime frequencies of OC spectrum disorders (p=0.03). OCD is a heterogeneous disorder and that the presence of specific comorbid diagnoses that predate the onset of OCD may influence its clinical presentation and course over the lifetime.     

Treatment strategies for obsessive-compulsive disorder

Importance of the field: In the last decades, the treatment of obsessive-compulsive disorder (OCD) has improved significantly with the introduction into the clinical practice of the selective serotonin reuptake inhibitors (SSRIs): this has led to a renewed interest in this condition and development of appropriate therapeutic strategies, including non-pharmacological techniques.

Areas covered in this review: The aim of this paper is to present a comprehensive and critical review of pharmacological and non-pharmacological treatments usually adopted in the management of OCD. MEDLINE and PubMed (1980 – 2009) databases were searched for English-language articles by using the following keywords: OCD, clomipramine, SSRIs, resistance, predictor of response, cognitive-behavioral therapy, exposure and response prevention, repetitive transcranial magnetic stimulation, deep brain stimulation, neurosurgery, electroconvulsive therapy.

What the reader will gain: The reader will gain an exhaustive review of the advantages and disadvantages of the treatments usually adopted in OCD, with a special focus on resistance and clinical features that can be used as predictors of response.

Take home message: Obsessive-compulsive disorder is a common psychiatric condition that can be adequately managed with the currently available therapeutic options. Although a certain percentage of patients do not achieve complete clinical remission, improvement of some of their core symptoms permits them to live more satisfying lives and to reach a better social adjustment.     

Recent advances in obsessive-compulsive disorder

A growing body of evidence from clinical phenomenology, including associated disorders, brain imaging, and neuropharmacologic studies, links the classic psychiatric syndrome of obsessive-compulsive disorder (OCD) to basal ganglia dysfunction and to the serotonin system. At present, OCD is the psychiatric syndrome for which a specific neurologic dysfunction is most strongly suggested, and for which a particularly compelling animal model has been found. It is proposed that dysfunction of basal ganglia-thalamic frontal cortical loops produce "positive" symptoms of excessive grooming, checking, and doubt most common in OCD. Perhaps most intriguing are preliminary data from clinical trials that a spectrum of other abnormal behaviors resembling excessive grooming in both animals and humans may be related to OCD. An ethologic perspective is suggested.     

Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder.

Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p < 0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.     

Ongoing lithium treatment prevents relapse after total sleep deprivation.

Forty bipolar depressed inpatients underwent three consecutive cycles of total sleep deprivation (TSD). At the beginning of the study, 20 patients were free of psychotropic drugs and 20 had been receiving lithium medication for at least 6 months. Mood was rated on the Hamilton Rating Scale for Depression before and after TSD; perceived mood changes during treatment were evaluated with self-administered visual analog scales. Patients undergoing long-term lithium treatment showed a significantly better response to TSD as rated on both scales: 13 of 20 patients (vs. 2 of 20 patients without lithium) showed a sustained response during a follow-up period of 3 months. This preliminary evidence of a positive interaction of TSD and long-term lithium treatment could be explained by a synergistic effect of both treatments on brain serotonergic function, possibly via a desensitization of 5-hydroxytryptamine-1A inhibitory autoreceptors.