Issues in the monopharmacotherapy and polypharmacotherapy of obsessive-compulsive disorder

Polypharmacotherapy is again becoming common place in clinical practice. Obsessive-compulsive disorder (OCD) as a single primary diagnosis is responsive exclusively to the serotonin reuptake inhibitors (SRIs) and this fact forms the major evidence supporting a central role for 5-HT (serotonin) in the pathogenesis of the disorder. Presently, the highly potent serotonin reuptake inhibitors clomipramine, fluoxetine, fluvoxamine, and paroxetine are the only agents approved by the Food and Drug Administration (FDA) for OCD, but there is evidence that other SRIs, such as sertraline, are also effective. Because OCD is often treatment refractory and highly comorbid with other psychiatric disorders, the use of polypharmacotherapy can be justified. Other serotonergic medications such as lithium, buspirone, trazodone, or fenfluramine may be useful as adjuvant treatments in treatment-refractory OCD and adjuvant antipsychotics are useful in tic disorders, personality disorders, and psychotic disorders. The usefulness of polypharmacotherapy should be tempered by adverse effects including the serotonin syndrome, withdrawal phenomena, extrapyramidal side effects, and drug-drug interactions.     

Treating obsessive-compulsive disorder among substance abusers: A guide.

Explores psychotherapeutic and pharmacologic approaches for the treatment of obsessive–compulsive disorder (OCD), and explains how these interventions can be integrated into a substance abuse treatment plan. Behavior therapy is the most effective treatment for OCD, using an exposure and response prevention paradigm. Five steps are recommended for treating substance abusers with OCD: (1) psychodiagnostic assessment, (2) assessment of symptom type and severity, (3) psychoeducational therapy, (4) developing a hierarchy of anxiety-evoking stimuli, and (5) treating OCD patients with exposure and response prevention. Four heterocyclic drugs with potent serotonin-reuptake inhibitor properties (clomipramine, fluoxetine, fluvoxamine, and sertraline) have also shown consistent effectiveness in reducing OCD symptoms. A case example is provided of a 37-yr-old male substance abuser seeking therapy for contamination fears and washing rituals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Decreased family accommodation associated with improved therapy outcome in pediatric obsessive–compulsive disorder.

Pediatric obsessive–compulsive disorder (OCD) is a chronic, disabling condition that affects both patients and their families. Despite the identification of efficacious treatments (e.g., cognitive–behavioral therapy and selective serotonin reuptake inhibitor medications), not all patients respond fully. The purpose of the present study was to examine whether the amount of family accommodation provided to pediatric patients with OCD is associated with treatment outcome, and whether decreases in accommodation are associated with improved outcome. The sample consisted of 49 youths (6–18 years of age), who participated in 14 sessions of family-based cognitive–behavioral therapy for OCD, and their parents. Participants completed measures at pretreatment and posttreatment. Results indicate that family accommodation was prevalent among families of pediatric patients with OCD and that such accommodation was associated with symptom severity at pretreatment. In addition, decreases in family accommodation during treatment predicted treatment outcome, even when controlling for pretreatment OCD severity–impairment. Results suggest that the level of accommodation provided by the family may indicate an important obstacle to, or predictor of, treatment outcome in pediatric OCD. Directions for future research are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of serotonin in obsessive-compulsive disorder

BACKGROUND: Serotonin may play a role in the pathophysiology of obsessive-compulsive disorder (OCD) because of the anti-obsessional effect of selective serotonin reuptake inhibitors (SSRIs). METHOD: The literature is reviewed on knowledge of the role of serotonergic neurons in brain function, studies on monoamine metabolites in cerebrospinal fluid (CSF), various stress neuropeptides, neuroendocrine and behavioural challenge after administration of direct and indirect serotomimetic compounds, and neuroanatomical data on brain circuits organising behaviour. RESULTS: In most of the OCD cases analysed, CSF 5-hydroxyindoleacetic acid and homovanillic acid concentrations do not significantly differ from age-corrected controls. However, a relationship appears to exist between pre-treatment levels of these metabolites and clinical response to drugs acting on the serotonin transporter. Abnormalities in CSF arginine vasopressin, corticotropin-releasing hormone, oxytocin and somatostatin levels have been reported in OCD. Long-term treatment with high-doses of clomipramine, fluvoxamine, and fluoxetine tend to correct these neuropeptide abnormalities. CONCLUSIONS: We hypothesise that continuous treatment with SSRIs alters serotonin turnover and neuropeptide expression patterns in OCD-entertaining functional forebrain/midbrain circuits.     

Treatment of obsessive-compulsive spectrum disorders with SSRIs

BACKGROUND: Obsessive-compulsive spectrum disorders (OCSDs) are now recognised as distinct diagnostic entities related to obsessive-compulsive disorder (OCD). The features of OCSDs and OCD overlap in many respects including demographics, repetitive intrusive thoughts or behaviours, comorbidity, aetiology and preferential response to anti-obsessional drugs such as the selective serotonin reuptake inhibitors (SSRIs). METHOD: Literature was reviewed and preliminary data from various studies were re-examined to assess the relationship between compulsivity and impulsivity, and between OCD and OCSDs. RESULTS: OCSDs include both compulsive and impulsive disorders and these can be viewed as lying at opposite ends of the dimension of risk avoidance. Compulsiveness is associated with increased frontal lobe activity and increased serotonergic activity, while impulsiveness is associated with reduced activity of these variables. Neural circuits affected by serotonergic pathways have been identified and pharmacological challenge of OCSD patients with serotonin receptor agonists have supported the involvement of serotonergic processes. CONCLUSIONS: SSRIs such as fluvoxamine have established efficacy in OCD and preliminary studies indicate that they are also effective in OCSDs. The features of three specimen OCSDs--body dysmorphic disorder, pathological gambling and autism--and their treatment with SSRIs are reviewed.     

Inhibition of Listeria monocytogenes in a pork product by a Lactobacillus sake strain

Fluoxetine has been reported to suppress food intake in animal models of feeding. Fluoxetine increases extracellular serotonin in the brain. 5HT1A autoreceptors regulate synaptic levels of serotonin. A combination of a 5HT1A receptor antagonist and fluoxetine has been previously reported to enhance extracellular levels of serotonin over what is obtained with fluoxetine alone. Thus, a combination of fluoxetine and a 5HT1A antagonist could enhance the ability of fluoxetine to suppress appetite. Fluoxetine was tested in a model of feeding, in which CD-1 mice were trained to drink sweetened condensed milk. Fluoxetine was found to attenuate milk drinking, in a dose-dependent manner, at doses greater than 10 mg/kg, i.p. A 10 mg/kg dose of fluoxetine, which was ineffective by itself, was then combined either with 5-hydroxytryptophan (5HTP), a serotonin precursor, or with S(-) pindolol, a 5HT1A/beta adrenergic receptor antagonist or with LY206130, a more selective 5HT1A receptor antagonist. These treatment paradigms resulted in significant attenuation of the consumption of sweetened condensed milk. Since fluoxetine has been shown to be useful in the treatment of eating disorders and to promote weight loss in obese humans, although at doses greater than those required for the treatment of depression, a combination of fluoxetine with a 5HT1A receptor antagonist could be of clinical utility in the treatment of eating disorders and obesity.     

Early prenatal direct gene diagnosis of cystic fibrosis in a twin pregnancy and subsequent selective termination

This study was designed to demonstrate a role of serotonin in the anticonvulsant effect of fluoxetine, a serotonin reuptake inhibitor, in genetically epilepsy-prone rats. When varied doses of 5-hydroxytryptophan (12.5, 25, 50 mg/kg) were administered i.p. along with a fixed dose of fluoxetine (15 mg/kg) to severe seizure genetically epilepsy-prone rats, the severity of audiogenic seizures was decreased dose-dependently, and the combination treatment also produced a marked potentiation of the anticonvulsant effect when compared with administration of either drug alone. Pretreatment of severe seizure genetically epilepsy-prone rats with p-chlorophenylalanine depleted brain serotonin and reduced the anticonvulsant effectiveness of fluoxetine. By using intracerebral microdialysis, the depletion of serotonin after p-chlorophenylalanine treatment was confirmed by measuring thalamic extracellular serotonin and 5-hydroxyindoleacetic acid concentrations during basal release and in response to a challenge dose of fluoxetine. We concluded that serotonergic transmission may be involved in the anticonvulsant effect of fluoxetine in severe seizure genetically epilepsy-prone rats.     

Kappa-opioid receptor stimulation quickens pathogenesis of compulsive checking in the quinpirole sensitization model of obsessive-compulsive disorder (OCD).

Repeated injections of the D?/D? dopamine agonist, quinpirole, induce locomotor sensitization and compulsive checking behavior in rats, a phenomenon that may constitute an animal model of obsessive- compulsive disorder (OCD). Considering that the co-joint treatment with quinpirole and the kappa opioid receptor agonist U69593 potentiates locomotor sensitization to quinpirole, the present study examined whether such co-stimulation of kappa and dopamine receptors also enhances compulsive checking and whether dopamine receptor supersensitivity mediates the augmentation effects. Results showed that co-treatment of quinpirole and U69593 had a robust accelerating effect on the acquisition of sensitized locomotion and compulsive checking but that the effects on the expression of quinpirole sensitization were behavior dependent, with increased magnitude of locomotion but not of compulsive checking. Quinpirole and even U69593, which by itself did not induce sensitization, increased the proportion of dopamine D? receptors in the high-affinity state (D? High) in the nucleus accumbens and striatum, indicating that elevation of D? High is not sufficient to account for sensitization or compulsive checking. The animal model findings point to a potential role of kappa opioid systems in hastening the pathogenesis of OCD and to the possibility that distinct brain regions may mediate the development and the expression of compulsive checking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intensive Cognitive Behavioral Therapy for Pediatric Obsessive Compulsive Disorder: A Treatment Protocol for Mental Health Providers.

The authors describe a protocol for intensive cognitive behavioral therapy (I-CBT) for children and adolescents with obsessive- compulsive disorder (OCD). After a review of pediatric OCD and efficacious treatments, the rationale for an intensive approach to treatment is provided along with findings in the extant literature. Subsequently, a session by session outline of I-CBT for pediatric OCD is provided. Finally, a case example of this treatment approach is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Different roles for serotonin in anti-obsessional drug action and the pathophysiology of obsessive-compulsive disorder

BACKGROUND: There is a major role for serotonin in the mechanism of anti-obsessional drug action. Drugs that block uptake of noradrenaline are not effective in the treatment of obsessive-compulsive disorder (OCD), while drugs that potently bock serotonin reuptake are effective. While enhancement of serotonin neurotransmission is clearly involved in the treatment of OCD, the role of serotonin in the pathophysiology of OCD is less clear. METHOD: This paper provides a brief, focused review of the literature regarding treatment of OCD, the effects of drugs with selective action at various serotonin receptors and results of neurotransmitter depletion studies in patients with OCD. RESULTS: Some patients with OCD may experience remission of OCD symptoms during intoxication with psychedelic drugs that have potent 5-HT2A/2C agonist activity. These findings, coupled with results from serotonin depletion studies in depressed and OCD patients, suggest that enhancement of serotonin neurotransmission may underlie both antidepressant and anti-obsessional drug action, although the targeted brain areas may differ. CONCLUSIONS: OCD may not involve a dysfunction of the serotonin system. Rather, it is more likely to involve a dysfunction of specific brain circuits, particularly in the frontal cortex. Modulation of these circuits by serotonin neurons may underlie the specific action of anti-obsessional drugs.     

Cytokine production in obsessive-compulsive disorder

Cytokine production was previously demonstrated to be reduced in untreated major affective patients. In addition, recovery from depression following clomipramine (CMI) treatment was accompanied by the restoration of interleukin-1 beta (IL-1 beta) and interleukin-3-like activity (IL-3-LA) to normal range. In the present study we assessed the in vitro production of IL-1 beta IL-2, and IL-3-LA by peripheral blood mononuclear cells (PBMC) in 11 nondepressed patients with obsessive compulsive disorder (OCD) before and after 8 weeks of CMI treatment. Results were compared with those of 11 healthy subjects. CMI treatment induced a significant improvement in OCD symptoms. No alteration was observed in cytokine production in OCD patients before treatment as compared to control subjects. Moreover, 8 weeks of drug treatment had no effect on cytokine production. In conclusion, OCD per se, as well as CMI treatment, have no effect on interleukin production as measured in this study.     

Review of Fear of contamination: Assessment and treatment.

Reviews the book, Fear of Contamination: Assessment and Treatment by Stanley Rachman (2006). As a renowned expert on obsessive compulsive disorder (OCD), Professor Rachman's contributions have shaped current psychological theory, research, and treatment of OCD more than any other contemporary psychologist. The current book, Fear of Contamination, adopts the author's current emphasis on fine-grained analyses of OCD, digging deep into the unique phenomenology of specific obsessional concerns. Based on his prior cognitive formulations for obsessions, Dr. Rachman's present book proposes a new cognitive-behavioural model for another OCD subgroup that has been neglected in recent years, those with fears of contamination. It begins with a convincing argument for taking a fresh look at our understanding and treatment of contamination OCD. Throughout the remainder of the book, the author provides a fascinating and highly innovative analysis of contamination fears. Fear of Contamination is a well-written, authoritative, and innovative treatment manual for disease and contamination fears that is sure to set a new standard for research and treatment of this disorder. It is probably the most important book published in the last few decades on this particular subtype of OCD and it promises to stimulate our research and invigorate our treatment of this rather intransigent fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history

The distribution of obsessive compulsive symptoms was compared in 16 individuals with primary obsessive compulsive disorder (OCD) and 16 individuals with Gilles de la Tourette syndrome (GTS) and associated obsessive compulsive behaviors (OCB). The two groups showed significant differences in the distribution of OC symptomatology. Furthermore, those OCD probands who shared a similar symptom profile with GTS individuals all had a positive family history of OCD. All of the other OCD probands were isolated cases. Implications of this finding on the etiology and pathogenesis of the two disorders are discussed.     

Cognitive and behavioral therapies alone versus in combination with fluvoxamine in the treatment of obsessive compulsive disorder

The purpose of this treatment package design study was to investigate the differential efficacy of cognitive therapy or exposure in vivo with response prevention for obsessive compulsive disorder (OCD) versus the sequential combination with fluvoxamine. Patients with OCD (N = 117) were randomized to one of the following five conditions: a) cognitive therapy for weeks 1 to 16, b) exposure in vivo with response prevention for weeks 1 to 16, c) fluvoxamine for weeks 1 to 16 plus cognitive therapy in weeks 9 to 16, d) fluvoxamine for weeks 1 to 16 plus exposure in vivo with response prevention in weeks 9 to 16, or e) waiting list control condition for weeks 1 to 8 only. Assessments took place before treatment (pretest) and after 8 (midtest), and 16 weeks (posttest). In the first 8 weeks, six treatment sessions were delivered. During weeks 9 to 16, another 10 sessions were given. Thirty-one patients dropped out. Outcome was assessed by patient-, therapist- and assessor-ratings of the Anxiety Discomfort Scale, the Yale-Brown Obsessive Compulsive Scale, and the Padua Inventory-Revised. In contrast with the four treatments, after 8 weeks the waiting list control condition did not result in a significant decrease of symptoms. After 16 weeks of treatment, all four treatment packages were effective on these OCD ratings, but they did not differ among each other in effectiveness. In OCD, the sequential combination of fluvoxamine with cognitive therapy or exposure in vivo with response prevention is not superior to either cognitive therapy or exposure in vivo alone.     

Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin''s lymphoma

Little is known about the psychiatric diagnosis and treatment of adolescents who sexually offend. We therefore describe an adolescent sex offender who met DSM-IV criteria for multiple paraphilias (except for the age criterion), bipolar type II disorder, and OCD, whose paraphilic urges and behaviors, depression, and violent obsessions responded to open label fluoxetine after failing to respond to long-term residential treatment. Although only a single and uncontrolled observation, this case suggests that some adolescent sex offenders may in fact have paraphilias, and that paraphilias in adolescents, like those in adults, may respond to serotonin reuptake inhibitors.     

A flow cytometric assay for D8/17 B cell marker in patients with Tourette's syndrome and obsessive compulsive disorder

D8/17 is proving to be an important diagnostic and treatment tool in patients with Tourette's syndrome (TS) and obsessive compulsive disorder (OCD). The present study represents a direct comparison of immunofluorescence microscopy and flow cytometry in terms of their relative efficiency in the detection of the DB/17 B cell marker. Analysis of 41 patients with OCD or TS and 31 control subjects by immunofluorescence microscopy and flow cytometer demonstrated an average of 6.5% of D8/17-positive B cells in controls with an average of 19.6% in OCD patients. Using the flow cytometer, values of 6.2% for controls and 22.4% for OCD patients were obtained. The flow cytometer test was able to count many more cells, induce less operator error and offer faster analysis while correlating strongly with the microscopic technique. Overall in our sample, the FACS assay test has a sensitivity of 77% and a specificity of 87%. The ease of use and close correlation to disease activity makes this an ideal test for clinical laboratories.     

Fluoxetine tenth anniversary update: the progress continues

This tenth anniversary review/update of fluoxetine concentrates on the past 5 years of its clinical application. The mechanism of action of fluoxetine; its metabolism; its efficacy in patients with various diagnostic subgroups of depression, patients with coincident medical disease, children and adolescents with depression, patients with eating disorders, and patients with obsessive-compulsive disorder (OCD); its long-term (maintenance) efficacy; its side effects and toxicity; and pharmacoeconomic considerations are reviewed. Pharmacotherapy is currently the only proven method for treating major depressive disorder that is applicable to all levels of severity of major depressive illness. Since its introduction 10 years ago, fluoxetine has been available to psychiatrists, primary care physicians, and other nonpsychiatric physicians as full-dose effective pharmacotherapy for patients with depression. Fluoxetine has been widely prescribed by physicians knowledgeable in pharmacology and in the treatment of depression because of its proven efficacy (ie, equal to that of tricyclic antidepressants [TCAs]), its ease of administration (with full therapeutic dosing usually starting from day 1), its generally benign side-effect profile, its remarkable safety in over-dose, and its proven effectiveness in the most common depressed patient population--anxious, agitated, depressed patients--as well as in patients with various subtypes and severities of depression. In more recent years it has also proved effective in the treatment of bulimia, an entity for which only limited or inadequate treatment options had been previously available. In OCD, fluoxetine, with its more acceptable side-effect profile and greater ease of dosing, presents a favorable alternative to previous drug therapy and is useful in treating both obsessions and compulsions. Fluoxetine is currently recognized among clinicians as efficacious in treating anxiety disorders and is being used successfully in special depressed populations such as patients with medical comorbidity, elderly patients, adolescents, and children. Rapid discontinuation or missed doses of short-half-life selective serotonin reuptake inhibitors, TCAs, and heterocyclic antidepressants are associated with withdrawal symptoms of a somatic and psychological nature, which cannot only be disruptive, but can also be suggestive of relapse or recurrence of depression. In striking contrast to these short-half-life antidepressants, fluoxetine is rarely associated with such sequelae on sudden discontinuation or missed doses. This preventive effect against withdrawal symptoms on discontinuation of fluoxetine is attributed to the unique extended half-life of this antidepressant. Current studies show that the overall increased effectiveness of fluoxetine in treating depression compensates for its higher cost, compared with older drugs, by reducing the need for physician contact because of increased compliance and less need of titration, and by reducing premature patient discontinuation, thereby yielding fewer relapses, less recurrence, and less reutilization of mental health services.     

Computational model of obsessive-compulsive disorder: examination of etiologic hypothesis and treatment strategies

Research has shown that obsessive compulsive disorder (OCD) is related to structural and functional abnormalities in the brain, and several authors have organized these findings into theories of OCD neuropsychiatric dysfunction. In this paper, these theories were used to develop a neural network model of OCD. OCD symptoms were hypothesized to result from a hyperactive orbitofrontal-striato-thalamic-orbitofrontal neural loop. The network was constructed and trained with a backpropagation algorithm, and it was then used to assess etiologic theories of OCD (e.g., basal ganglia dysfunction, inadequate dopaminergic inhibitory influence on basal ganglia and excessive input from the limbic system). The network was also observed in analogues of the treatment of OCD with serotonergic medications and behavior therapy. Results show that a) the network behaved both normally and abnormally, depending on what combinations of perceptual, motivational, and neurochemical inputs were presented to it; b) several etiologic mechanisms produced changes in the networks' behaviors similar to patients' subjective experiences of OCD symptoms; and c) different treatment strategies, both those modeled as pharmacologic and behavioral therapies, produced reductions in simulated OCD symptoms.     

Differential responsiveness to fluoxetine during puberty.

In male golden hamsters (Mesocricetus auratus), attack frequency decreases during puberty. As serotonin inhibits offensive responses in adult hamsters, it is hypothesized that the serotonin system becomes upregulated in the hypothalamus during puberty. This hypothesis was tested through acute treatment with fluoxetine, a serotonin reuptake inhibitor, as well as through analysis of serotonin innervation in specific brain areas. In adults, fluoxetine treatment inhibited aggressive behavior. In juveniles, high doses of fluoxetine only reduced offensive responses (i.e., frequency and repetition of attacks), whereas low doses enhanced them. Juveniles also showed a dose-specific maturation of attack targets. In addition, the density of serotonin innervation of the hypothalamus was 20% higher in adult hamsters compared with juveniles. On the basis of these data, it is proposed that the developing serotonergic system shapes the development of offensive behaviors in male golden hamsters. (PsycINFO Database Record (c) 2010 APA, all rights reserved)