Higher serotonin transporter availability in early‐onset obsessive–compulsive disorder patients undergoing escitalopram treatment: A [11C]DASB PET study

Objective

Early‐onset obsessive–compulsive disorder (EOCD) and late‐onset obsessive–compulsive disorder (LOCD) are distinct subtypes of obsessive–compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet.

Methods

Six EOCD and 6 LOCD patients were enrolled. They underwent serial [¹¹C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug‐free binding potential of SERT was calculated by pharmacokinetic–pharmacodynamic modelling.

Results

In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = ?.580, p = .048) with age of onset of the disease, but not with the Yale–Brown Obsessive Compulsive Scale scores.

Conclusions

These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long‐term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients.     

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

Background  

Schedule-induced polydipsia (SIP), characterized by the development of excessive drinking under intermittent food-reinforcement schedules, has been proposed as a successful model for obsessive–compulsive disorder (OCD), schizophrenia, and alcohol abuse.     

The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder

Rationale  

In recent years, an increasing body of evidence points to the involvement of the glutamatergic system and specifically the glutamatergic ionotropic N-methyl-d-aspartate (NMDA) receptor in the pathophysiology of obsessive–compulsive disorder (OCD).     

Halometasone monohydrate (0.05%) in occupational contact dermatitis

Objective:

The impact of occupational contact dermatitis (OCD) is often underestimated because of underreporting, and its management is also inadequate, especially in developing countries. Topical corticosteroids have remained the first line treatment but till date, there is no study on efficacy and safety of halometasone in OCD, and there is a paucity of data on its comparative efficacy in allergic and irritant variety. This study aims to evaluate the efficacy and safety of halometasone in OCD and to compare its effect in allergic and irritant types of OCD.

Methods:

The present study is a prospective, interventional, single arm clinical study conducted on 150 patients of OCD. Detailed history and clinical examination was done at baseline, and all enrolled patients underwent patch test with the Indian Standard Battery of allergens. Eczema severity was assessed by the Investigator''s Global Assessment (IGA) scale, SCORing Atopic Dermatitis (SCORAD) index, and patient-oriented eczema measure (POEM). Change in quality of life was assessed by using the Dermatology Life Quality Index (DLQI). After baseline assessments, they were prescribed halometasone 0.05% ointment and were followed up after 4 weeks, and efficacy variables were evaluated.

Results:

At follow-up, 19 patients were lost, and data of 131 patients were analyzed. After 4 weeks of halometasone therapy, there was statistically significant (P < 0.001) improvement in SCORAD index, IGA, POEM, and DLQI. Considering improvement in IGA as treatment success criteria, treatment was found to be successful in 87.8%. Subgroup analysis revealed no significant difference in effect of halometasone in allergic and irritant OCD.

Conclusions:

Halometasone is efficacious with a good safety profile in patients with OCD, and there is no significant difference in efficacy of the drug in allergic and irritant OCD.KEY WORDS: Dermatology Life Quality Index, halometasone, Investigator''s Global, Assessment scale, occupational contact dermatitis, patient-oriented eczema measure, SCORing atopic dermatitis     

In a double-blind, randomized and placebo-controlled trial, adjuvant memantine improved symptoms in inpatients suffering from refractory obsessive-compulsive disorders (OCD)

Background

There is growing evidence that memantine, a noncompetitive N-methyl-d-aspartate receptor antagonist, may be applied as an add-on in treating patients suffering from obsessive–compulsive disorders (OCD). The aim of the present study was therefore to assess the effect of adjuvant memantine in a double-blind, randomized, and placebo-controlled study of the treatment of patients suffering from OCD.

Method

A total of 40 inpatients (32 females (80 %); mean age?=?31.25 years) suffering from OCD were randomly assigned to a treatment (administration of memantine) or a control group (placebo). Treatment lasted for 12 consecutive weeks. All patients were treated with selective serotonin re-uptake inhibitors or clomipramine. Patients completed the Yale–Brown Obsessive Compulsive Scale four times. Experts’ ratings consisted in clinical global impression (clinical global impressions (CGI), illness severity and illness improvement; two to three times). Liver enzymes SGOT and SGPT were also assessed (twice).

Results

Of the 40 inpatients approached, 29 completed the 12 consecutive weeks of the study. Of the 11 dropouts, 6 were in the target group and five in the control group. Symptoms significantly decreased across the period of the study, but particularly in the treatment compared with the control group (significant time?×?group interaction). Illness severity (CGI severity) also significantly decreased over time but more so in the treatment than in the control group (significant time?×?group interaction). Illness improvements (CGI improvements) were not significant.

Conclusions

The pattern of results from the present double-blind, randomized, and placebo-controlled study for the treatment of patients suffering from OCD suggests that adjuvant memantine does significantly and favorably impact on OCD.     

D2 and D3 dopamine receptor affinity predicts effectiveness of antipsychotic drugs in obsessive-compulsive disorders: a metaregression analysis

Rationale and objective

The relationship between clinically effective antipsychotic drugs in obsessive–compulsive disorders (OCD) and binding affinities to cloned dopamine and serotonin receptor subtypes was analyzed in an effort to clarify the contribution of individual receptor subtypes to medication response.

Methods

Meta-analysis was used to update previous meta-analyses of effectiveness data of add-on antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) in OCD. Twelve previously analyzed randomized controlled trials (RCTs) and one new RCT were included. We performed a metaregression using a mixed-effect model to examine the association between antipsychotic’s effectiveness and receptor affinity.

Results

A total of 5 treatment arms obtained from 13 RCTs (431 patients) were included in our study. The results of our metaregression showed a significant association between D2 and D3 dopamine receptor affinities and effectiveness in OCD (respectively, slope?=??0.36, p?=?0.01; and slope?=??0.50, p?=?0.01) whereas other dopamine receptors and serotonin receptors were not significantly associated.

Conclusions

These observations suggest that increasing D2 and D3 dopamine receptor binding affinities enhances antipsychotics’ effectiveness in obsessive–compulsive disorders.     

The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder

Rationale

In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive–compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse.

Objectives

The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, “compulsive” behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food.

Methods

The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10).

Results

Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model.

Conclusions

Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.     

Effects of the serotonergic agonist mCPP on male rats in the quinpirole sensitization model of obsessive–compulsive disorder (OCD)

Rationale

The serotonergic agonist, meta-chlorophenylpiperazine (mCPP), produces inconsistent effects on obsessive–compulsive disorder (OCD) symptoms, perhaps because clinical studies have not utilized a homogenous OCD subgroup of patients.

Objectives

This study aimed to evaluate mCPP effects on functional components of compulsive checking, using the quinpirole sensitization rat model of OCD.

Methods

In study 1, the effects of mCPP were evaluated in quinpirole rats with compulsive checking. Two experimental groups were co-injected with quinpirole (0.125 mg/kg) and mCPP (0.625 or 1.25 mg/kg), while one control group was co-injected with quinpirole (0.125 mg/kg) and saline and the other control group received co-injections of saline. In study 2, mCPP (0, 0.3125, 0.625, and 1.25 mg/kg) was administered repeatedly to naïve rats and induction of compulsive checking evaluated.

Results

mCPP significantly attenuated quinpirole-induced compulsive checking behavior by reducing vigor of checking (indexed by frequency of checking and length of check) and increasing rest after a bout of checking (indexed by time to the next checking bout), but it did not affect focus on the task of checking (indexed by recurrence time of checking and number of stops before returning to check). In naïve rats, mCPP did not induce compulsive behavior, but the highest dose reduced vigor of checking performance compared to saline controls.

Conclusions

mCPP did not exacerbate or induce compulsive checking behavior. Instead, it ameliorated compulsive checking by reducing vigor of checking and increasing post-checking satiety, without affecting focus on checking. Ameliorative effects of mCPP may involve 5HT_2A/2C receptors in substantia nigra pars reticulata that inhibit expression of motor vigor.     

Effects of chronic fluoxetine treatment on serotonin 1B receptor-induced deficits in delayed alternation

Rationale

Obsessive-compulsive disorder (OCD) patients show overactivation of the orbitofrontal cortex and deficits in cognitive tasks that require proper orbitofrontal functioning including delayed alternation tests of spatial working memory. We recently showed that OCD-like behavior is induced in mice by activating orbitofrontal serotonin 1B receptors (5-HT1Bs). However, the role of 5-HT1Bs in delayed alternation remains unclear.

Objectives

We examined the effects of 5-HT1B receptor activation on delayed alternation task (DAT) performance. We also assessed the ability of an effective OCD treatment, fluoxetine, to prevent 5-HT1B-induced deficits in DAT performance.

Methods

Mice were tested on the DAT after acute treatment with saline, 3 or 6 mg/kg RU24969 (5-HT1B/1A agonist), 0.3 or 3 mg/kg 8-OH-DPAT (5-HT1A agonist), or co-injection with 3 mg/kg RU24969 and 5 mg/kg GR127935 (5-HT1B/1D antagonist). Separate mice were pretreated chronically (28 days) with 10 mg/kg fluoxetine and then tested on the DAT after acute treatment with 3 mg/kg RU24969, 0.3 mg/kg 8-OH-DPAT, or saline.

Results

Both doses of RU24969 decreased accuracy and increased latency on the DAT, and GR127935 blocked RU24969-induced effects on accuracy. The 0.3 mg/kg 8-OH-DPAT did not affect the DAT performance, whereas 3 mg/kg increased omissions on the DAT. Finally, RU24969-induced DAT deficits were absent in fluoxetine-pretreated mice.

Conclusions

We show that 5-HT1B receptor activation disrupts DAT performance in mice, and chronic fluoxetine pretreatment blocks these 5-HT1B-induced deficits. Our findings suggest that 5-HT1B receptors play an important role in modulating orbitofrontal-dependent delayed alternation. Moreover, 5-HT1B-induced DAT deficits may provide a mouse model for DAT deficits in OCD.     

Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive–compulsive symptoms

Rationale

Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive–compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology.

Objectives

This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms.

Methods

A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped.

Results

Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene–gene interaction model (p?=?0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F _{6, 137}?=?7.650, p?<?0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT.

Conclusions

These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.     

Separate mechanisms for development and performance of compulsive checking in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD)

Rationale

Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking.

Objectives

The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model.

Methods

Four groups of male rats (N?=?14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP.

Results

Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only.

Conclusions

Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.     

Effects of mood stabilizers on marble-burying behavior in mice

Rationale

Obsessive–compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD.

Objectives

In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior.

Methods

The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated.

Results

Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA_A receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA_B receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA_A receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg).

Conclusions

These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA_A receptor-dependent mechanism.     

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.     

A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation

Objective:

To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine.

Method:

A MEDLINE, Psycinfo and Web of Science search (1966-May 2009) was performed using the following keywords: agomelatine, melatonin, S20098, efficacy, safety, adverse effect, pharmacokinetic, pharmacodynamic, major depressive disorder, bipolar disorder, Seasonal Affective Disorder (SAD), Alzheimer, ADHD, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Obsessive-Compulsive Disorder (OCD), anxiety disorders and mood disorder.

Study collection and data extraction:

All articles in English identified by the data sources were evaluated. Randomized, controlled clinical trials involving humans were prioritized in the review. The physiological bases of melatonergic transmission were also examined to deepen the clinical comprehension of agomelatine’ melatonergic modulation.

Data synthesis:

Agomelatine, a melatonergic analogue drug acting as MT₁/MT₂ agonist and 5-HT_2C antagonist, has been reported to be an effective antidepressant therapy.

Conclusions:

Although a bias in properly assessing the “sleep core” of depression may still exist with current screening instruments, therefore making difficult to compare agomelatine’ efficacy to other antidepressant ones, comparative studies showed agomelatine to be an intriguing option for depression and, potentially, for other therapeutic targets as well.     

Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population

Background

Elevated phospholipase A2 (PLA2) activity is reported to be involved in the development of schizophrenia. Further study revealed an association between PLA2 groups XIIA (PLA2G12A) polymorphism and patients with schizophrenia in a northeast Chinese Han population.

Objective

This study will further examine whether PLA2G12A rs3087494 polymorphism is associated with patients with schizophrenia in a southern Chinese Han population.

Methods

This polymorphism was genotyped in 438 patients with schizophrenia (diagnosed according to Diagnostic and Statistical Manual of Mental Disorders‐IV) and 876 healthy controls using a case–control design. Demographic and clinical data were collected in all subjects.

Results

The allele and genotype frequencies of PLA2G12A rs3087494 polymorphism significantly differed between groups (both, p < .001). These differences still were significant by adjusting for sex and age. However, there was no difference in age at onset among 3 genotype groups in patients with schizophrenia by adjusting for the variables (F = 0.22, p = .80). Stepwise multivariate regression analysis showed that this polymorphism was not associated with age at onset in patients with schizophrenia (β = .008, t = .07, p = .94).

Conclusions

Our results indicated that even though PLA2G12A rs3087494 polymorphism did not influence age at onset in patients with schizophrenia, it may play an important role in the susceptibility to schizophrenia in a southern Chinese Han population.     

Mitochondrial Antioxidants Alleviate Oxidative and Nitrosative Stress in a Cellular Model of Sepsis

Purpose  

Mitochondrial dysfunction plays a key role in sepsis.     

Clinical trials during pregnancy: what has been done

Objective  

We describe clinical trials conducted in pregnant women.     

Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT

Rationale  

Pharmacokinetics of melatonin in children might differ from that in adults.     

Short circuit: Disaggregation of adrenocorticotropic hormone and cortisol levels in HIV‐positive,methamphetamine‐using men who have sex with men

Objective

This study examined if methamphetamine use alone (METH + HIV?) and methamphetamine use in combination with HIV (METH + HIV+) were associated with hypothalamic‐pituitary‐adrenal (HPA) axis dysregulation as well as insulin resistance relative to a nonmethamphetamine‐using, HIV‐negative comparison group (METH‐HIV?).

Methods

Using an intact groups design, serum levels of HPA axis hormones in 46 METH + HIV? and 127 METH + HIV+ men who have sex with men (MSM) were compared to 136 METH‐HIV? men.

Results

There were no group differences in prevailing adrenocorticotropic hormone (ACTH) or cortisol levels, but the association between ACTH and cortisol was moderated by METH + HIV+ group (β = ?0.19, p < .05). Compared to METH‐HIV? men, METH + HIV+ MSM displayed 10% higher log₁₀ cortisol levels per standard deviation lower ACTH. Both groups of methamphetamine‐using MSM had lower insulin resistance and greater syndemic burden (i.e., sleep disturbance, severe depression, childhood trauma, and polysubstance use disorder) compared to METH‐HIV? men. However, the disaggregated functional relationship between ACTH and cortisol in METH + HIV+ MSM was independent of these factors.

Conclusions

Further research is needed to characterize the bio‐behavioral pathways that explain dysregulated HPA axis functioning in HIV‐positive, methamphetamine‐using MSM.     

Environmental-induced differences in corticosterone and glucocorticoid receptor blockade of amphetamine self-administration in rats

Rationale  

Rats raised in isolation self-administer more amphetamine than rats raised in enrichment.