Alessio Simonetti

Functional neuroimaging in obsessive-compulsive disorder.

Background and Aim: Obsessive-compulsive disorder (OCD) is a severe, highly prevalent and chronically disabling psychiatric disorder that usually emerges during childhood or adolescence. This paper aims to review the literature on functional neuroimaging in OCD, analysing the reported dysfunctional connectivity in the corticostriatothalamocortical circuitry. Method: This study included papers published in peer-reviewed journals dealing with functional imaging in OCD. Results: Striatal dysfunction, mainly of the caudate nucleus, leads to inefficient thalamic gating, resulting in hyperactivity within the orbitofrontal cortex (intrusive thoughts) and the anterior cingulate cortex (non-specific anxiety). Compulsions consist of ritualistic behaviours performed to recruit the inefficient striatum and neutralise unwanted thoughts and anxiety. Functional neuroimaging findings are discussed against the background of specific cognitive impairments, mainly regarding visuospatial processing, executive functioning and motor speed. Cognitive deficits are partial and specific, matching imaging data. Conclusions: Several studies have targeted brain regions hypothesised to be involved in the pathogenesis of OCD, showing the existence of dysfunctional connectivity in the corticostriatothalamocortical circuitry. Improvements in spatial resolution of neuroimaging techniques may contribute to a better understanding of the neurocircuitry of OCD and other anxiety disorders.

The role of memantine in the treatment of psychiatric disorders other than the dementias: A review of current preclinical and clinical evidence

Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer’s disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer’s disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.

Suicide in a large population of former psychiatric inpatients

Aims:  The aim of this study was to identify predictors of completed suicide in a wide sample of psychiatric inpatients receiving retrospective and prospective DSM‐IV diagnoses.

Mixed Depression: Clinical Features and Predictors of Its Onset Associated with Antidepressant Use

Background: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. Methods: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. Results: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. Conclusions: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

An improved simple LC–MS/MS method for the measurement of serum aripiprazole and its major metabolite

BACKGROUND AND OBJECTIVES Current liquid chromatographic tandem mass spectrometry (LC-MS/MS) methods to measure serum levels of aripiprazole (Ar) and dehydroaripiprazole (DHAr) are sensitive, but difficult to use in a hospital context. We aimed to develop a rapid LC-MS/MS method allowing reliable level measurement in the presence of co-administered drugs, withdrawing samples from 22 patients with acute agitation receiving 9.75 mg aripiprazole IM injection. METHOD We developed a sensitive and selective HPLC-MS/MS method to measure serum Ar and DHAr levels in a hospital laboratory, requiring minimal sample preparation and inferior sample volume compared to previous LC-MS/MS methods. Analytes were separated on a reversed-phase HPLC (run-time, 10 min). A triple quadrupole tandem mass spectrometer was used for quantitative analysis in positive mode by a multiple reaction monitoring. Samples were drawn 2, 4, 6, and 24h post-injection. RESULTS Calibration curves (2-1000 ng/mL for Ar and 3.5-500 ng/mL for DHAr) were linear, with mean correlation coefficient >0.9998. Within- and between-day precision and accuracy were within 10%. Mean recovery was 95.2 ± 4.5% for Ar and 97.6 ± 7.2% for DHAr. Ar and DHAr peaks were not affected by other co-administered psychotropic drugs. CONCLUSION Our method measured Ar and DHAr concentrations reliably, simply and rapidly without employing many reagents, as currently existing methods.

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.

The wnt pathway in mood disorders

Objectives: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. Methods: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. Results: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. Conclusions: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

Childhood traumatic experiences of patients with bipolar disorder type i and type II

BACKGROUND Childhood trauma is an important environmental stressor associated with bipolar disorders (BD). It is still not clear if it is differently distributed between BD I and BD II. Therefore, the aim of this research was to investigate the distribution patterns of childhood trauma in BD I and BD II. In this perspective, we also studied the relationship between childhood trauma and suicidality. METHODS We assessed 104 outpatients diagnosed with BD I (n=58) or BD II (n=46) according to DSM-IV-TR criteria and 103 healthy controls (HC) matched for age, sex and education level. History of childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ). RESULTS All patients with BD had had more severe traumatic childhood experiences than HC. Both BD I and BD II patients differed significantly from HC for trauma summary score and emotional abuse. BD I patients differed significantly from HC for sexual abuse, and BD II differed from HC for emotional neglect. BD I and BD II did not significantly differ for any type of trauma. Suicide attempts were linked to both emotional and sexual abuse in BD I and only to emotional abuse in BD II. Emotional abuse was an independent predictor of lifetime suicide attempts in BD patients. LIMITATIONS The reliability of the retrospective assessment of childhood trauma experiences with the CTQ during adulthood may be influenced by uncontrolled recall bias. CONCLUSIONS The assessment of childhood trauma, which has great clinical importance because of its strong link with suicidality, can unveil slight differences between BD subtypes and HC.

Personality Changes After Toscana Virus (TOSV) Encephalitis in a 49-Year-Old Man: A Case Report

ABSTRACT Toscana virus (TOSV) infection may often cause symptomatic meningitides and encephalitides. These usually subside in few days and their sequelae do not last for more than few weeks. We here report the case of a 49-year-old man who developed encephalitis after being bitten by phlebotomi in a region near southern Tuscany, where TOSV is endemic, and who developed postencephalitic seizures and subsequently, persistent personality alterations, characterized by sexually dissolute behavior and aggressiveness. One year after infection, the patient needs a combination of an SSRI antidepressant and a mood stabilizer/anticonvulsant to obtain less than optimal symptom improvement. This points to the need of establishing better preventive measures in Tuscany and nearby regions.

Hippocampal subfield volumes in short- and long-term lithium-treated patients with bipolar I disorder.

Patients diagnosed with bipolar disorder (BP) may experience hippocampal atrophy. Lithium exposure has been associated with increased hippocampal volumes. However, its effects on hippocampal subfields remain to be clarified.