Emanuela Mundo

Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.

RationaleRecent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl-d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3′ untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl-d-aspartate 2B) were associated with OCD in affected families.ObjectivesThe objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design.MethodsUsing the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity.ResultsUnder a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested (P=0.014). In addition, there was a significant positive association with OCD diagnosis (P=0.002) for the 5072G–5988T haplotype under the recessive model.ConclusionsAlthough preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

Clinical variables related to suicide attempts in schizophrenic patients: a retrospective study

In this study, we investigated the possible association between clinical or pharmacological variables and suicidal behavior in a sample of chronic schizophrenia or schizoaffective disorder patients. One hundred and three patients with a DSM-III-R diagnosis of chronic schizophrenia or schizoaffective disorder were studied. The sample was subdivided in two subsamples according to the presence/absence of suicidal attempts lifetime. The main demographic and clinical variables retrospectively collected were analyzed and compared between the two groups. Attempters had a significantly higher rate of nicotine abuse or dependence (chi-square=3.900, df=1, p<0.05, Odds Ratio (O.R.)=3.4), were more likely to have or have had lifetime major depressive episodes (chi-square=10.258, df=1, p<0.002, O.R.=6.5), were more likely to have a duration of untreated psychosis (DUP) > or =1 year (chi-square=6.228, df=1, p<0.02, O.R.=12.5), and were more frequently prescribed typical antipsychotics (chi-square=3.979, df=1, p<0.05, O.R.=6.5) than patients without suicidal attempts lifetime. Further investigations on larger samples and with prospective designs are warranted, particularly with respect to the role of early intervention and atypical antipsychotic treatment in reducing suicide risk in schizophrenic patients.

Intramuscular Preparations of Antipsychotics Uses and Relevance in Clinical Practice

Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called ‘depot’, are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism.Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics.Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose.Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation.To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, especially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.

Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression

OBJECTIVES The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in bipolar depression. The present study aimed to assess the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) combined with brain navigation in a sample of bipolar depressed subjects. METHODS Eleven subjects with bipolar I or bipolar II disorder and major depressive episode who did not respond to previous pharmacological treatment were treated with three weeks of open-label rTMS at 1 Hz, 110% of motor threshold, 300 stimuli/day. RESULTS All subjects completed the trial showing a statistically significant improvement on the 21-item Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impression severity of illness scale (ANOVAs with repeated measures: F = 22.36, p < 0.0001; F = 12.66, p < 0.0001; and F = 10.41, p < 0.0001, respectively). In addition, stimulation response, defined as an endpoint HAM-D score reduction of > or =50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score < or = 8). Partial response (endpoint HAM-D score reduction between 25% and 50%) was achieved by 3/11 patients. No manic/hypomanic activation was detected during the treatment according to Young Mania Rating Scale scores (ANOVAs with repeated measures: F = 0.62, p = 0.61). Side effects were slight and were limited to the first days of treatment. CONCLUSIONS Augmentative low-frequency rTMS of the right DLPFC combined with brain navigation was effective and well tolerated in a small sample of drug-resistant bipolar depressive patients, even though the lack of a sham controlled group limits confidence in the results.

Clinical and subclinical body dysmorphic disorder.

Background The aim of the study was to define the main demographic and clinical characteristics of Body Dysmorphic Disorder (BDD) and subclinical BDD (sBDD) in a sample derived by a screening survey done on a population of individuals referring to aesthetical medicine centers. Method 487 subjects referring to hospital centers for aesthetical medicine were administered the SCID-I and the Yale-Brown Obsessive-Compulsive Scale adapted for BDD (BDD-YBOCS). The sample was thus sub-divided in three sub-samples: 1) BDD, 2) sub-clinical BDD, and 3) controls. The main demographic and clinical variables were considered and compared between the BDD and the sBDD samples. Results As previously reported, the prevalence of BDD and sBDD was 6.3 % and 18.4 %, respectively. The most frequent comorbid diagnosis in both BDD and sBDD patients and their relatives was Obsessive-Compulsive Disorder (OCD). A higher severity of symptoms was found in male BDD patients, while no gender-related differences were found in the sBDD group. Suicidal ideation was found in 12.1 % of the sBDD and in 49.7 % of the BDD patients. Conclusions These results support the hypothesis of BDD and sBDD belonging to the OCD spectrum, and appear to advise long-term follow-up studies on the course and the prognosis of sBDD.

Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open-label study

BACKGROUND The literature on the use of quetiapine for the treatment of bipolar disorder (BD) is limited to case reports, and there are no systematic studies on the efficacy of quetiapine in the prophylactic treatment of BD. The aim of the present study was to compare the efficacy of flexible doses of quetiapine and well established mood stabilizers in the maintenance treatment of BD. METHODS Twenty-eight DSM-IV BD outpatients were consecutively recruited into the study and were randomized to receive one of two open-label treatments, with quetiapine or classical mood stabilizers at flexible doses for 12 months. Clinical assessment was carried out using BPRS, CGI, YMRS and the 21-item HAM-D at baseline (T0) and every 2 months until the end of the study. ANOVAs with repeated measures were applied to the rating scale scores considering the time and the treatment group as main factors. RESULTS All patients experienced a significant improvement on the BPRS, CGI and HAM-D scores, with no significant side-effects and a good compliance. LIMITATIONS This study should be considered preliminary given the small sample size investigated and the open-label design. CONCLUSIONS If these results will be replicated on larger samples and in controlled studies, there could be relevant implications for the use of quetiapine as an alternative maintenance treatment for BD.

Effect of adjuvant pindolol on the antiobsessional response to fluvoxamine: a double-blind, placebo-controlled study.

On the basis of recent results indicating that adjuvant pindolol has the positive effect of shortening latency to antidepressant response to selective serotonin reuptake inhibitors, the primary aim of our study was to evaluate the effect of pindolol on latency to antiobsessional response to fluvoxamine. Fifteen non-depressed obsessive-compulsive inpatients (six men and nine women) were consecutively recruited and randomly assigned to an 8-week standardized double-blind treatment with fluvoxamine and pindolol (group A) or fluvoxamine and placebo (group B). Patients were assessed weekly using rating scales for obsessive-compulsive disorder [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), National Institute of Mental Health Obsessive-Compulsive Scale], co-occurent depressive symptoms (Hamilton Depression Scale) and global function (Clinical Global Improvement), from baseline to the end of the study. In accordance with data from the literature, response to treatment was defined as a reduction in YBOCS total scores of ± 35% and a score on the ‘global improvement’ item of the Clinical Global Improvement of < 3. Data were analysed using analyses of variance with repeated measures performed on YBOCS and Hamilton Depression Scale scores to evaluate the mean quantitive response within and between groups and, additionally, employing a survival analysis to compute the percentage of responders within each group. Neither quantitative nor qualitative analysis revaled any differences between the two treatment groups, and pindolol did not shorten the latency of antiobsessional response to fluvoxamine. The results of this preliminary study indicate that different biological mechanisms underly the antiobsessional and antidepressant responses to fluvoxamine.

Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder.

INTRODUCTION The aim of the present study was to investigate the impact of the duration of untreated illness (DUI)-defined as the time elapsing between the onset of generalized anxiety disorder (GAD) and the first adequate pharmacologic treatment-on treatment response and clinical course in a sample of subjects with GAD. METHODS One hundred patients with GAD, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria, were enrolled and their main demographic and clinical features collected. Patients were then treated with selective serotonin reuptake inhibitors or venlafaxine for 8 weeks in open-label conditions. Treatment response and other clinical variables were analyzed after dividing the sample into two groups according to DUI (DUI <or=12 months and DUI >12 months). RESULTS When the DUI was computed with respect to the first antidepressant treatment (DUI-AD), a higher improvement (Clinical Global Impressions-Severity of Illness scale) after the pharmacologic treatment was found in the group with a shorter DUI (analysis of variance with repeated measures: time effect F=654.975, P<.001; group effect: F=4.369, P=.039). When computed with respect to the first treatment with benzodiazepines (DUI-BDZ), the two groups did not show any significant difference in treatment response (time effect: F=652.183, P<.001; group effect: F=0.009, P=.924). In addition, patients with a longer DUI (DUI-BDZ or DUI-AD) showed an earlier age at onset, a longer duration of illness and a higher rate of comorbid psychiatric disorders with onset later than GAD. CONCLUSION Results from this preliminary study seem to suggest that a shorter DUI-AD may determine a better response to pharmacologic treatment in patients with GAD, and that a longer DUI (DUI-BDZ and DUI-AD) may be associated to a worse clinical course. Further investigation on the relationship between DUI and GAD is needed.

Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder : A 4-year follow-up naturalistic study

BACKGROUND The aim of this naturalistic study was to compare the effectiveness of quetiapine and classical mood stabilizers, as mono- or combination therapy, in the long-term treatment of Bipolar Disorder (BD). METHODS 232 DSM-IV BD I (n=91) or BD II (n=141) patients, treated and followed up for four years, were studied. Mood stabilizers were chosen by the treating psychiatrists on the basis of their clinical judgement. The sample was subdivided into 6 treatment groups: quetiapine (n=41), lithium (n=39), sodium valproate (n=73), lamotrigine (n=31), quetiapine plus lithium (n=25), and quetiapine plus sodium valproate (n=23). Throughout the 4-year follow-up period patients were assessed monthly, or whenever a recurrence occurred, by the administration of HAMD-21 and of the YMRS. Primary outcome measures were the duration of euthymia and the cumulative proportion of subjects who maintained euthymia. Kaplan-Meier survival analyses were done to tabulate and compare the differences in survival distributions across the different treatment groups (Log-Rank Mantel-Cox test). RESULTS The combined treatments with quetiapine plus lithium or sodium valproate were more effective overall in maintaining euthymia, (percentages of patients who maintained euthymia: 29.3% for quetiapine, 46.2% for lithium, 32.9% for sodium valproate, 41.9% lamotrigine, 80% for quetiapine plus lithium, and 78.3% for quetiapine plus sodium valproate). In addition, quetiapine monotherapy was as effective as lithium monotherapy or combination treatment with lithium or sodium valproate in preventing the recurrence of major depressive episodes. LIMITATION The main limitations of the study are the lack of randomized, controlled conditions and the low doses of quetiapine used. CONCLUSION If the results from this study will be replicated, there will be important implications for the use of quetiapine in the long-term treatment of BD.

Diagnosis and treatment of obsessive-compulsive disorder and related disorders.

Obsessive‐compulsive disorder (OCD) is currently recognised as one of the most common psychiatric disorders as well as one of the most disabling of all medical disorders. Obsessive‐compulsive related disorders (OCRDs), often comorbid with OCD, include many distinct psychiatric conditions (i.e. some somatoform disorders, eating disorders, impulse control disorders and some neurological conditions) which have overlapping symptoms and compulsive qualities with OCD. Although effective treatments exist, OCD and related disorders are often underdiagnosed and undertreated. Serotonin reuptake inhibitors (SRIs) and cognitive behavioural therapy (CBT) represent the first‐line treatment for OCD and related disorders. However, the time and the doses of the medications used in the treatment of OCD and related disorders differ from those recommended in depressive disorders. In addition, remission is not common for patients with OCD and related disorders in clinical practice, and poor responders as well as refractory cases may benefit from different treatment strategies including integrated treatment, pharmacological augmentation and brain stimulation techniques.