Brassinosteroids Mitigate Cadmium Effects in Arabidopsis Root System without Any Cooperation with Nitric Oxide.

The heavy metal cadmium (Cd) affects root system development and quiescent center (QC)-definition in Arabidopsis root-apices. The brassinosteroids-(BRs)-mediated tolerance to heavy metals has been reported to occur by a modulation of nitric oxide (NO) and root auxin-localization. However, how BRs counteract Cd-action in different root types is unknown. This research aimed to find correlations between BRs and NO in response to Cd in Arabidopsis's root system, monitoring their effects on QC-definition and auxin localization in root-apices. To this aim, root system developmental changes induced by low levels of 24-epibrassinolide (eBL) or by the BR-biosynthesis inhibitor brassinazole (Brz), combined or not with CdSO4, and/or with the NO-donor nitroprusside (SNP), were investigated using morpho-anatomical and NO-epifluorescence analyses, and monitoring auxin-localization by the DR5::GUS system. Results show that eBL, alone or combined with Cd, enhances lateral (LR) and adventitious (AR) root formation and counteracts QC-disruption and auxin-delocalization caused by Cd in primary root/LR/AR apices. Exogenous NO enhances LR and AR formation in Cd-presence, without synergism with eBL. The NO-signal is positively affected by eBL, but not in Cd-presence, and BR-biosynthesis inhibition does not change the low NO-signal caused by Cd. Collectively, results show that BRs ameliorate Cd-effects on all root types acting independently from NO.

Functional Magnetic Resonance Imaging Correlates of First-Episode Psychoses during Attentional and Memory Task Performance.

BACKGROUND: The nature of the alteration of the response to cognitive tasks in first-episode psychosis (FEP) still awaits clarification. We used activation likelihood estimation, an increasingly used method in evaluating normal and pathological brain function, to identify activation changes in functional magnetic resonance imaging (fMRI) studies of FEP during attentional and memory tasks. METHODS: We included 11 peer-reviewed fMRI studies assessing FEP patients versus healthy controls (HCs) during performance of attentional and memory tasks. RESULTS: Our database comprised 290 patients with FEP, matched with 316 HCs. Between-group analyses showed that HCs, compared to FEP patients, exhibited hyperactivation of the right middle frontal gyrus (Brodmann area, BA, 9), right inferior parietal lobule (BA 40), and right insula (BA 13) during attentional task performances and hyperactivation of the left insula (BA 13) during memory task performances. CONCLUSIONS: Right frontal, parietal, and insular dysfunction during attentional task performance and left insular dysfunction during memory task performance are significant neural functional FEP correlates.

Systematic Review of Clozapine Cardiotoxicity.

Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

The impact of periventricular white matter lesions in patients with bipolar disorder type I.

INTRODUCTION: White matter hyperintensities (WMHs) are one the most common neuroimaging findings in patients with bipolar disorder (BD). It has been suggested that WMHs are associated with impaired insight in schizophrenia and schizoaffective patients; however, the relationship between insight and WMHs in BD type I has not been directly investigated. METHODS: Patients with BD-I (148) were recruited and underwent brain magnetic resonance imaging (MRI). Affective symptoms were assessed using Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS17); the presence of impaired insight was based on the corresponding items of YMRS and HDRS17. RESULTS: Multiple punctate periventricular WMHs (PWMHs) and deep WMHs (DWMHs) were observed in 49.3% and 39.9% of the cases, respectively. Subjects with lower insight for mania had significantly more PWMHs (54.6% vs 22.2%; p < 0.05) when compared to BD-I patients with higher insight for mania. The presence of PWMHs was independently associated with lower insight for mania: patients who denied illness according to the YMRS were 4 times more likely to have PWMHs (95% CI: 1.21/13.42) than other patients. CONCLUSIONS: Impaired insight in BD-I is associated with periventricular WMHs. The early identification of BD-I subjects with PWMHs and impaired insight may be crucial for clinicians.

Are 5-HT3 antagonists effective in obsessive-compulsive disorder? A systematic review of literature.

OBJECTIVE: The purpose of this literature database search-based review was to critically consider and evaluate the findings of literature focusing on efficacy and safety of 5-HT3 antagonists in the treatment of obsessive-compulsive disorder (OCD), so as to test whether preclinical data match clinical therapeutic trials. DESIGN: The PubMed database has been searched for papers on 5-HT3 antagonists and OCD in humans and for animal models of OCD and 5-HT3 receptors. RESULTS: Of the clinically tested 5-HT3 receptor antagonists, ondansetron has been used to treat OCD in five therapeutic studies, whereas granisetron only in one recent trial. Both showed some efficacy in open studies and superiority to placebo in double-blind studies, along with fair safety. No animal OCD model directly implicated 5-HT3 receptors. CONCLUSIONS: Overall, results indicate some utility, but the available literature is too scanty to allow for valid conclusions to be drawn. The mismatch between animal models of obsessive-compulsive disorder and clinical data with 5-HT3 antagonists needs more clinical data to ensure that it is not an artefact.

Deep transcranial magnetic stimulation for treatment-resistant bipolar depression: a case report of acute and maintenance efficacy.

Deep Transcranial Magnetic Stimulation (dTMS) is currently being evaluated as a possible treatment for several neuropsychiatric disorders and has been demonstrated as a safe and effective procedure. This case presents a patient with bipolar depression that has been treated with 20 daily consecutive dTMS sessions and with one dTMS session every 2 weeks for the following 3 months. Depressive symptoms improved rapidly and response was maintained during the next 6 months; cognitive performances also improved. This report suggests that add-on dTMS may help overcoming drug-resistance in bipolar depression and protect from subsequent bipolar episodes of any polarity.

[Olanzapine in manic/mixed patients with or without substance abuse]. / Olanzapina in pazienti maniacali o misti con o senza abuso di sostanze.

AIM: To evaluate the efficacy of olanzapine in patients in their manic/mixed phase with or without comorbidity with substance abuse/dependence disorder. METHODS: In this observational, controlled, prospective study, 60 patients with a DSM-IV-TR diagnosis of bipolar disorder, manic/mixed episode (30 patients with and 30 patient without comorbidity with a substance abuse/dependence disorder) were treated with olanzapine, evaluated at discharge, and followed-up for 8 weeks. Efficacy of olanzapine was assessed by comparing the proportion of responders (an at least 50% drop in Young Mania Rating Scale [YMRS] score from baseline) and remitters (YMRS ≤ 12 and Hamilton Depression Rating Scale [HAM-D] ≤ 8) in both groups. Craving and days of abuse/use were assessed with Visual Analogue Scale (VAS) and Time-line Follow-Back (TLFB), respectively. RESULTS: Differences in response and remission percentages were statistically not significant at discharge and during follow-up. A reduction of days of abuse has been observed in the drug-abuse group, while craving was only slightly decreased. DISCUSSION: These results suggest that olanzapine is effective in both groups and its efficacy in reducing the days of abuse appears to be independent from its action on craving.

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.

Insight and awareness as related to psychopathology and cognition.

BACKGROUND: Insight affects adherence and treatment outcome and relates to cognitive impairment and psychopathology. We investigated the relationship of insight with cognition in patients with major depression, schizophrenia and bipolar disorder in acute psychiatric care, long-term inpatient, and outpatient settings. METHODS: Eighty-one patients (women, 59.5%; age, 45.9 ± 13.5 years; 27 in each setting group; 33.3% with DSM-IV bipolar disorder, 39.5% with unipolar major depression, and 27.2% with schizophrenia) underwent the Wisconsin Card Sorting Test (WCST) to test flexibility, clinician-rated Scale to Assess Unawareness of Mental Disorder (SUMD), and self-rated Insight Scale (IS) to assess insight/awareness. RESULTS: Poor performance on the WCST correlated with higher SUMD scores such as current psychiatric illness unawareness, impaired symptom attribution, unawareness of medication effect, or of social consequences, but not with IS scores. The latter correlated with days on continuous treatment. Patients receiving psycho-education showed greater symptom awareness compared to patients treated with drugs alone. Cognitive flexibility and diagnostic category did not correlate. Poor insight corresponded with severe mental illness, particularly acute psychosis. CONCLUSIONS: Treatment setting specificity reflects psychopathology and severity. Insight is inversely proportional to illness severity and cognitive flexibility, which is also affected by psychopathology. Limitations comprise group heterogeneity, cross-sectional design, and limited sample size.

Factors affecting interindividual differences in clozapine response: a review and case report.

OBJECTIVE: Clozapine is the most powerful new­generation antipsychotic. Although this drug leads to great therapeutic benefits, two types of undesirable conditions frequently occur with its use: side effects and resistance to treatment. Therapeutic drug monitoring of clozapine would be very useful to avoid both these situations. The necessity of monitoring the therapy is the result of a wide interindividual variability in the metabolism of clozapine. In this review, we highlight all the conditions underlying this variability, analyzing them one by one. METHODS: Relevant literature was identified through a search of MEDLINE and PubMed. In addition, the case of a treatment­resistant patient with accelerated metabolism of clozapine is reported as representative of utility of therapeutic drug monitoring in terms of clozapine dose adjustment. RESULTS: Genetic polymorphisms of cytochrome P450 enzymes and of neurotransmitter receptors; drug interactions; interactions of clozapine with other substances such as food and drink; smoking; and nonmodifiable variables such as age, ethnicity, and gender have been examined in relation to the existing scientific literature. The laboratory techniques that clinicians could use to identify these variables and adequate therapies are also reviewed.

Clozapine-induced gastroesophageal rumination in 22q11.2 Deletion Syndrome. A case report on gastroesophageal side effects management without renouncing clozapine's effectiveness.

Despite entailing more severe and uncommon side effects in 22q11.2DS compared to idiopathic schizophrenia, we strongly believe that clozapine should continue to be considered the gold standard for all treatment-resistant schizophrenia, even in 22qDS.

Persistent interferon-ß-1b-induced psychosis in a patient with multiple sclerosis.

Interferon-ß is used in patients with multiple sclerosis to reduce autoimmunity; although other psychiatric side-effects are common, in contrast to interferon-alpha, psychosis has been reported only once. A patient with multiple sclerosis developed auditory hallucinations, paranoid delusions, and increased aggressiveness after 16 months of treatment with interferon-ß-1b, 250 mg every other day. He responded after about one month to antipsychotic treatment, but tended to relapse upon dose reduction, and after 2 years still needs antipsychotics to control his symptoms. Because there was no change in his magnetic resonance imaging between pre- and post-treatment with interferon, we concluded that psychosis was more related to interferon treatment than to the underlying disease.

[Patients with mood disorders admitted for a suicide attempt to an emergency ward]. / Suizidversuche bei affektiven Störungen in der Notaufnahme.

AIM: The aim of the study was to assess risk factors associated with suicidal behaviour in adult patients suffering from major mood disorders (MD) and admitted to a hospital emergency department (ED). METHODS: Participants were 283 adult patients with MDs admitted to an ED between 2006-2007. Comparisons were 675 adult patients with other DSM-IV-TR Axis I disorders. Patients undertook a complete psychiatric assessment including DSM-IV-TR diagnostic interview. RESULTS: MD patients were almost 2 times more likely to have been admitted for a suicide attempt (odds ratio [OR]=1,97 [95% confidence intervals [CI]: 1,29/3,03]; p< 0,01), to report suicidal ideation at the psychiatric interview (OR=1,75 [95%CI: 1,01/3,03]; p< 0,05), than their pairs without MDs. MD patients admitted for a suicide attempt were more than 3 times more likely to report suicidal ideation at the psychiatric interview (OR=3,26 [95%CI: 1,46/7,30]; p< 0,01), than nonattempter MD patients. DISCUSSION: Suicide behavior is one of the major reasons of use of EDs in MDs, and suicide risk is still high in the next hours after suicide attempt and admission in the ED. Therefore ED's interventions for mood disorders and suicidality must be carefully planned.

Social cognition deficit and genetic vulnerability to schizophrenia in 22q11 deletion syndrome.

INTRODUCTION: 22q11.2 microdeletion syndrome (22q11DS) is associated with a 25% risk of psychotic onset. MATERIALS AND METHODS: The sample consist of 120 subjects: 39 schizophrenics (SCZ); 20 siblings of schizophrenic patients (SIB); 34 22q11DS non-psychotic patients (DEL); 17 22q11DS psychotic patients (DEL_scz); 30 control subjects (CS). Social cognition was evaluated with the awareness of social interference test. Intelligence Quotient (IQ) was calculated with Wechsler Adult Intelligence Scale. TASIT (Awareness of Social Inference Test) performance was analyzed via MANOVA, including IQ as covariate. RESULTS: Group and IQ showed significant effect (p < 0.001; p = 0.037). The only TASIT variables where IQ showed no effect were paradoxical sarcasm; sincerity; lie. In sincerity, CS group shows a better performance than both 22q11DS groups (p < 0.05). In paradoxical sarcasm and lie, CS group performed better than each clinical group (p < 0.05). Regarding lie, DEL group was worst also respect to SCZ group (p = 0.029). CONCLUSIONS: Our results show a specific social cognition deficit in 22q11DS and schizophrenia.

Add-on high frequency deep transcranial magnetic stimulation (dTMS) to bilateral prefrontal cortex in depressive episodes of patients with major depressive disorder, bipolar disorder I, and major depressive with alcohol use disorders.

BACKGROUND: Dorsolateral prefrontal cortex (DLPFC) is critically involved in mood and alcohol use disorders. OBJECTIVE: We aimed to investigate the safety of intervention with add-on bilateral prefrontal high-frequency deep transcranial magnetic stimulation (dTMS) and between-group differences in treatment response in patients with different types of depressive episodes, including major depressive episodes in the course of major depressive disorder (MDD), bipolar disorder, type I (BD-I), and MDD with alcohol use disorder (MDAUD). METHODS: We conducted a 6-month open-label study, involving 82 patients with DSM-5 Depressive Episode. Of these, 41 had diagnosis of MDD, 20 BD-I, and 21 MDAUD. All patients received standard drug treatment and add-on dTMS over the bilateral DLPFC with left prevalence for four weeks, with five sessions in each week. We rated mood state with the Hamilton Depression Rating Scale (HDRS) at baseline, one-month, and six-month follow-up visits. RESULTS: Mean total HDRS scores dropped from 22.8 (SD = 5.9) at baseline to 10.4 (SD = 3.6) at 1 month, to 10.0 (SD = 4.5) at 6 months, while response/remission were 70.73% (N = 58) and 19.51% (N = 16) at 1 month and 76.83% (N = 63) and 32.93% (27) at 6 months, respectively, with no between-group differences. No patient experienced any side effects. CONCLUSIONS: High-frequency DLPFC dTMS was well tolerated and did not significantly differ on improvement of depression in MDD, BD-I, and MDAUD.

Impairment in Social Functioning differentiates youth meeting Ultra-High Risk for psychosis criteria from other mental health help-seekers: A validation of the Italian version of the Global Functioning: Social and Global Functioning: Role scales.

Social and occupational impairments are present in the schizophrenia prodrome, and poor social functioning predicts transition to psychosis in Ultra-High Risk (UHR) individuals. We aimed to: 1) validate the Italian version of the Global Functioning: Social (GF: S) and Global Functioning: Role (GF: S) scales; 2) evaluate their association with UHR criteria. Participants were 12-21-years-old (age, mean=15.2, standard deviation=2.1, male/female ratio=117/120) nonpsychotic help-seekers, meeting (N=39) or not (N=198) UHR criteria. Inter-rater reliability was excellent for both scales, which also showed good to excellent concurrent validity, as measured by correlation with Global Assessment of Functioning (GAF) scores. Furthermore, GF:S and GF: R were able to discriminate between UHRs and non-UHRs, with UHRs having lower current scores. After adjusting for current GAF scores, only current GF:S scores independently differentiated UHR from non-UHR (OR=1.33, 95%CI: 1.02-1.75, p=0.033). Finally, UHR participants showed a steeper decrease from highest GF:S and GF: R scores in the past year to their respective current scores, but not from highest past year GAF scores to current scores. GF:S/GS: R scores were not affected by age or sex. GF:S/GF: R are useful functional level and outcome measures, having the advantage over the GAF to not confound functioning with symptom severity. Additionally, the GF:S may be helpful in identifying UHR individuals.

Low-dose acetazolamide in the treatment of premenstrual dysphoric disorder: a case series.

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.

Depression and affective temperaments are associated with poor health-related quality of life in patients with HIV infection.

INTRODUCTION: Human immunodeficiency virus (HIV) represents one of the most chronic and debilitating infections worldwide. Hopelessness and affective temperaments (mood that is characteristic of an individual's habitual functioning) may play important roles in the health-related quality of life (HRQoL) of patients with HIV. The purpose of this study was to examine affective temperaments in a sample of patients with HIV, the impact of hopelessness on HRQoL, and associations among HRQoL, hopelessness, and affective temperaments. METHODS: The study involved 88 participants who were administered the short- form health survey (SF-36), the Beck hopelessness scale (BHS), the suicidal history self-rating screening scale (SHSS), the Gotland male depression scale (GMDS), and the temperament evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A). RESULTS: Patients with a poorer HRQoL reported more severe depression and hopelessness than patients with a higher HRQoL. Patients with a poorer HRQoL also had higher scores on all dimensions of the TEMPS-A with a depressive component compared to patients with a higher HRQoL. The small sample size in this study limits the generalizability of the findings. CONCLUSION: Patients with a poorer HRQoL were more depressed and also at an increased risk of suicide as indicated by the more severe hopelessness they reported compared to patients with higher HRQoL. These patients were also more likely to have depressive affective temperaments than those with a higher HRQoL.

Increased serum Dickkopf-1 levels in drug-abusing psychotic patients.

BACKGROUND: Dickkopf-1 (DKK1) is an inhibitor of the canonical Wnt pathway, which is known to be impaired in both psychotic and neurodegenerative disorders. Here, we examined serum DKK1 levels as an indicator of ongoing neurodegeneration in psychotic patients, with or without a recent or current history of drug abuse. METHODS: We measured serum DKK1 levels by ELISA in 22 inpatients with psychosis and no history of drug abuse, 22 with psychosis and drug abuse, and 16 controls. We rated psychopathology using the following rating scales: the Positive and Negative Syndrome Scale (PANSS); the Clinical Global Impressions (CGI) severity scale; and the Global Assessment of Functioning (GAF) scale. Extrapyramidal motor symptoms were assessed by the Simpson-Angus Neurological Rating Scale (NRS). RESULTS: Inpatients with psychosis and comorbid substance abuse showed significantly higher serum DKK1 levels than inpatients with psychosis and no comorbid substance abuse or controls. Comorbid patients had earlier onset, longer duration of psychosis, and more severe extrapyramidal motor symptoms. However, we did not find any significant correlation between DKK1 levels and rating scale scores. CONCLUSION: Psychosis led to elevated serum DKK1 levels, and substance abuse led to a further increase. Knowing that there is a correlation between brain and blood levels of DKK1, we speculate that the observed increase in DKK1 levels reflects drug-induced neurotoxicity in our patients.