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Clozapine is the only antipsychotic compound indicated for refractory-schizophrenia. However, it is associated with emergent metabolic dysregulation and cardiovascular risk which may lead to mortality. In this study we aimed to explore predictors for mortality in a large cohort of schizophrenia patients treated with long-term clozapine, using the electronic medical records of the largest health care provider in Israel. Among 27,929 patients diagnosed with schizophrenia, 1817 were prescribed clozapine during the years 2012-2014. We compared patients who survived (n=1705) and patients who died (n=112) during the 3-year follow-up period. Socio-demographic background, cardiovascular morbidity, medication prescriptions and health-care utilization were compared between groups. Cox proportional hazard models were used to assess the association of variables with survival. Chronic hypertension was found to be the only metabolic factor associated with significant hazard ratio (HR) for mortality (HR: 1.55 95% CI: 1.03-2.34). Moreover, those who died had more prevalent ischemic heart disease (14% vs 3%, p0.005) as well as more frequent hospitalizations (0.01±0.02 vs 0.11±0.18 average per month, p0.005), for longer periods (2.22±9.87 vs 20.38±33.76 days per month, p0.005). Among those who died, less patients received prescriptions of statins for hyperlipidemia (13.7% vs. 52.9% in survivors, p0.005) and hypoglycemics for diabetes mellitus (16.3% vs. 67.1% in survivors, p0.005). Inadequate treatment of metabolic syndrome, under chronic clozapine treatment, was found to be an independent predictor for mortality. Adequate rigorous regimen for diagnosis and treatment of metabolic risk factors, especially hyperlipidemia and diabetes mellitus, might lower complications rate and prolong life expectancy among this population.

Major depressive disorder (MDD) is associated with alterations in circulatory cytokines, in adults as well as in children and adolescents. Administration of selective serotonin reuptake inhibitors (SSRIs) to MDD pediatric patients modifies cytokine levels. However, most studies only assessed changes over a short time period. In this study, we evaluated long-term effects of the SSRI fluoxetine (FLX) in children and adolescents treated for anxiety and/or MDD, including a high-risk group with pre-treatment suicidality. The study group included ninety-two patients (35 boys and 57 girls) with MDD and/or anxiety disorders, aged 13.90 ± 2.41 years. All patients were treated with FLX and followed for 6 months. The study group included children with pretreatment suicidality (high-risk group;N = 62) and without pretreatment suicidality (N = 30) according to the Columbia Suicide Severity Rating Scale. Plasma concentrations of TNFα, IL-6, and IL-1β were measured by enzyme linked immunosorbent assays before and after six months of treatment. IL-6 and IL-1β significantly increased as a factor of time after 6 months of treatment. The elevation was statistically significant confined to children with pretreatment suicidality. Within the children with pretreatment suicidality, IL-6 levels increased significantly after 6 months only in the children who developed SSRI-associated suicidality. To summarize, an increase in IL-6 levels after 6 months of treatment may be associated with SSRI-emergent suicidality in children with pretreatment suicidality. Further studies are needed to clarify the role and mechanism(s) of IL-6 in the pathogenesis of this life-threatening adverse event.

Although antidepressants (ADs) are widely used in bipolar depression, there is weak evidence for their effectiveness and safety in this condition. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in bipolar disorder (BD). We compared rehospitalization rates of patients with BD-I depressive episode who were discharged with mood stabilizers (MSs) and/or atypical antipsychotics (AAPs) with or without adjunctive AD. Ninety-eight patients with BD-I who were hospitalized with a depressive episode between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates, as well as time to rehospitalization, according to treatment at discharge: MSs and/or AAPs with or without AD. Multivariable survival models adjusted for covariates known to influence rehospitalization were conducted. Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P = .001, power = 0.87 and 12.3% vs. 42.4%, P = .001, power = 0.89, respectively). Time to rehospitalization within 6-months and 1-year was significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P = .001 and 335.6 vs 252.3 days, P = .001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR = 0.081, 95% CI: 0.016-0.412, P = 0.002) and 1-year (HR = 0.149, 95% CI: 0.041-0.536, P = 0.004). Moreover, adjunctive-AD treatment did not increase rehospitalization rates of manic episode. In conclusion, adjunctive-AD therapy to MS/AAP at discharge from BD-I depressive episode hospitalization is associated with a lower rate of and a longer time to rehospitalization during a 1-year follow up period.

Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl- d -aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50 mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25–50 mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5 mg/kg ip) hyperactivity. PGW5 (25 mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50 mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. Conclusions: PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression.

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10 mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.

Introduction Increasing evidence exists indicating an association of DHEA and DHEA-S blood levels with psychosis, however many of the findings remain contradictory based on different phases of the illness, different treatments and at a range of ages. To date no studies exist investigating the levels of these neurosteroids in adolescents with psychosis. Such an investigation would be important in order to exclude effects of chronic illness, long-term treatment and repeated hospitalizations. Method Peripheral venous blood samples for DHEA, DHEA-S and cortisol determination were collected from first-time hospitalized adolescents with diagnoses of schizophrenia as well as from patients with conduct disorder. Patients were rated with the Positive and Negative Syndrome Scale (PANSS), the Hamilton Scale for depression (HAM-D), the Overt Aggression Scale (OAS) and the impulsivity scale (IS). Results DHEA levels in adolescents with schizophrenia were significantly higher than in patients with conduct disorder (p = 0.002). Blood levels of DHEA and DHEA-S in schizophrenia correlated with the total PANSS scores (both p

Neuroleptic-induced akathisia (NIA) is a common, sometimes incapacitating adverse effect of anti-psychotic medication. Zolmitriptan is a selective 5-HT(1D) agonist. We aimed to determine its anti-NIA efficacy in comparison to propranolol. Thirty-three neuroleptic-treated patients were randomly allocated in a double-blind design to receive either 7.5 mg/d of zolmitriptan or 120 mg/d of propranolol for 3 consecutive days, followed by 3 days without any anti-NIA treatment. Patients were assessed at baseline and on days 3 and 7 by the Barnes Akathisia Rating Scale (BARS), PANSS, HAMD, HAMA, Pulse, and Blood Pressure. Both groups showed improvement of akathisia (BARS) along the treatment period, with significant effect for time but not for group. No significant differences were found between the groups in all other measurements. Taken together, zolmitriptan was found to be as effective as propranolol for the treatment of NIA. Further placebo-controlled studies are warranted.

Reduced brain γ-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D2L Kiz = 0.066 nM, D2S Ki = 0.062 nM, 5-HT2A Ki = 0.21 nM). PK data revealed that BL-1020 penetrated the brain. Conclusions: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation

Accumulating data indicates that neurosteroids can modulate aggressive behavior. The aim of the present study was to examine neurosteroid blood levels in delinquent adolescent boys as compared to normal healthy controls. Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol blood levels were measured in 16 delinquent adolescent (age 15.72 ± 0.95 years) with conduct disorder (CD) and 11 normal controls (16.82 ± 1.83 years). Severity of aggressive behavior was assessed by the Child Behavior Checklist (CBCL) and the Overt Aggression Scale (OAS). The delinquent adolescents tended to have higher DHEA-S levels than the normal control group (p = 0.054). DHEA and cortisol levels did not differ between the two groups. The interaction between neurosteroids ( especial DHEA-S) and genetic, developmental and environmental factors in juvenile delinquency merits further investigation.

Background: Accumulating data suggest that schizophrenia patients' mental status might be modulated by their core/brain temperature. Hence, we intended to assess in vivo brain temperature (Tb) of schizophrenia patients vs. healthy subjects and to evaluate its potential association with patients' mental status. Methods: Absolute values of Tb were measured in 9 neuroleptic-treated schizophrenia patients and 10 healthy comparison subjects using 1H magnetic resonance spectroscopy (MRS). Values were extracted by measuring the chemical shift between the peaks of water and N-acetyl-aspartate in the 1H MRS spectra. Results: A substantial (about 1.1 °C) and significantly higher occipital–frontal temperature-gradient was found in the schizophrenia patients compared to the healthy controls (1.27 °C vs. 0.18 °C; p = 0.032). Furthermore, a trend was found between the above mentioned occipital–frontal temperature-gradient in the schizophrenia patients and the severity of their psychopathology, as assessed by the total Positive and Negative Syndrome Scale (PANSS) scores (r = 0.61; p = 0.08). Conclusions: Our findings corroborate previous results indicating putative correlation between core/brain temperature and the mental status of schizophrenia patients, emphasizing the possible role of within patients decreased frontal temperature and a significant occipital–frontal temperature-gradient as modulators of psychopathology. In addition, the MRS technique used for brain temperature assessment seems to be a potential non-invasive method to assess in vivo absolute Tb in schizophrenia.

We evaluated the effect of DHEA complementary treatment in opiate addicts undergoing detoxification. DHEA (100 mg/day) or placebo was added to the routine medication protocol in a randomized, double blind controlled study. Follow-up for 12 months was conducted. Two separate DHEA-treated subgroups were identified by the Fuzzy clustering method: one showed statistically significant improvement in the severity of withdrawal symptoms, depression and anxiety scores (n=34; p0.001 for all) and the other subgroup deteriorated in all measures (n=15). DHEA at the end of the detoxification program showed a tendency towards correlation with the duration of abstinence (r=0.6843; p0.05; n=6), while a negative correlation was obtained with the cortisol level (r=-0.900; p=0.005, n=8). The completion-rate of the DHEA-improved subgroup was greater than in the DHEA-deteriorated subgroup (64.7% vs. 33.3%, respectively). The influence of supplementary DHEA treatment was mostly effective in heroin addicts who had not previously used either cocaine or benzodiazepines and who had experienced only few withdrawal programs.

Antidepressants facilitate neuroplasticity by stimulating trophic factors. This study evaluated the effect of fluoxetine (FLX) treatment on insulin-like growth factor-1 (IGF-1) in the rat brain and its role in the effect of FLX on cognition. IGF-1 receptor (IGF-1R) protein expression and IGF-1 mRNA levels were assessed in rat frontal cortex (FC) and hippocampus, in FLX-treated [15 mg/kg, orally; 3 (acute) or 21 (repeated) days] male Wistar rats. Rats were subjected to the Morris Water Maze test. Acute FLX administration decreased IGF-1 mRNA levels in the FC and hippocampus and increased IGF-1R levels in the FC. Repeated FLX increased both mRNA and IGF-1R levels in the FC. Repeated, but not acute, FLX treatment decreased IGF-1 mRNA in the hippocampus. FLX did not affect cognitive performance. Thus, repeated FLX treatment leads to upregulation of IGF-1 system is FC. It is possible that FLX affect FC neuroplasticity through activation of the IGF-1 system.

Glutamate disruption is thought to have a major role in schizophrenia brain processes, possibly involving NMDA hypofunction. The metabotropic glutamate receptors are distributed in brain regions related to schizophrenia and seem to affect glutamate release in a moderate way. Compounds modulating these receptors are being investigated in animal models of schizophrenia, in an attempt to discover new antipsychotics. This article reviews the current research data regarding the role of these receptors in schizophrenia animal models. It was found that more research was done on Group I and II metabotropic receptors while investigation of group III receptors is still trailing behind. Accumulating evidence shows that mGluR5 antagonists by themselves do not necessarily disrupt pre-pulse inhibition (PPI), but can exacerbate disruption of PPI caused by MK-801 and PCP, while positive modulation of this receptor has beneficial effects on these models of psychosis. Group II agonists are also showing beneficial effects in animal models. It seems that metabotropic glutamate receptor modulators could be developed into a novel treatment of schizophrenia by altering glutamate release, thus overcoming the putative NMDA hypofunction. Although the implications from these pre-clinical studies to human schizophrenia patients are premature, the data obtained with some compounds point to promising results for drug development. More studies, with agents active at other mGluRs in animal models and schizophrenia patients as well as with human subjects are needed in order to clarify the role of the metabotropic glutamate receptors in the pathophysiology and pharmacotherapy of schizophrenia.

It has been shown that the atypical antipsychotic drug clozapine increases the levels of the neurosteroid allopregnanolone in the rat brain. The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been demonstrated to be involved in the process of steroid biosynthesis, in peripheral steroidogenic tissues as well as in glia cells in the brain. In the current study, we investigated the influence of chronic treatment with clozapine and other antipsychotics (thioridazine,sulpiride and risperidone) on TSPO binding in cell cultures and rat tissues. Clozapine significantly increased TSPO binding density in C6 rat glioma cells and in MA-10 mouse Leydig tumor cells, while the antipsychotic sulpiride had no effect on TSPO binding density in both cell lines. In addition, clozapine, but not sulpiride, significantly increased progesterone synthesis by MA-10 Leydig tumor cells. In an animal experiment, male Sprague–Dawley rats were treated with clozapine (20 mg/kg), risperidone (0.5 mg/kg), thioridazine (20 mg/kg), or sulpiride (20 mg/kg) for 21 days, followed by 7 days of withdrawal. Clozapine induced significant increases in TSPO binding in brain and peripheral steroidogenic tissues, whereas the other antipsychotics did not show such pronounced effects on TSPO binding. Our results suggest that TSPO may be involved in the modulation of steroidogenesis by clozapine.

Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes. There is accumulating evidence on their role in adult psychopathology, including Alzheimer disease, schizophrenia, mood disorder, anxiety disorders and post-traumatic stress disorder. Little is known, however, about the possible role of neurosteroids in child and adolescent psychopathology although there is increasing evidence for their critical role from the early stages of brain development until adolescence. In this review we focus on the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents. Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit. The complex interaction between neurosteroids, neurodevelopment, life-events, genetics and mental disorders in children and adolescents merits further investigation.

The "phospholipid hypothesis" attributes a pathophysiologic role to the polyunsaturated fatty acid (PUFA) composition of phospholipids in depression. The aim of the present study was to determine whether the hypothesis is relevant to social anxiety disorder (SAD). The study sample consisted of 27 untreated, nondepressed patients with SAD (DSM-IV) and 22 controls. Severity of SAD was assessed with the Liebowitz Social Anxiety Scale (LSAS). Erythrocyte PUFA concentrations were measured by gas-liquid chromatography. Concentrations of most n-3 PUFAs were lower in the patients: 18:3n-3 by 32% (p0.002), 20:3n-3 by 34%, 20:5n-3 by 36% (all p0.001) and 22:6n-3 by 18% (p = 0.002). No significant differences were observed in other fatty acids. Significant inverse correlations were obtained between levels of n-3 PUFAs and LSAS scores. In conclusion, the phospholipid hypothesis may apply to SAD, thereby opening new therapeutic options. The robust relationship between low erythrocyte n-3 PUFA concentrations and SAD justifies exploration of relevant neuropathophysiological mechanisms.

Objective: The goals of this study were to determine whether alterations in serum dehydroepiandrosterone (DHEA), its sulfated conjugate (DHEAS), androstenedione, testosterone, and progesterone concentrations occur in schizophrenia patients compared with healthy controls over two months, and their associations with psychopathology, emotional distress, and antipsychotic treatment. Method: Serum hormones were repeatedly determined for 21 antipsychotic-treated male DSM-IV schizophrenia patients and 14 healthy controls. Observations were at four time points: upon entry into the study, and after 2, 4 and 8 weeks. Results: In schizophrenia patients compared with healthy controls serum concentration of DHEA and androstenedione found increased, but that of DHEAS decreased, while progesterone and testosterone showed normal levels. Schizophrenia patients were also characterized by elevated androstenedione / DHEAS molar ratios, and reduced DHEAS / DHEA and testosterone / androstenedione molar ratios compared with healthy controls. Concentrations and molar ratios of serum hormones did not significantly change during the study either among schizophrenia patients, or healthy controls. Among patients alterations in DHEA, DHEAS and androstenedione were associated with emotional distress, anxiety, dysphoric mood, positive and activation symptoms, serum prolactin levels, but were not related to age, antipsychotic agents, and extrapyramidal side effects. Conclusions: Alterations in DHEA metabolism in schizophrenia are attributed to the distress, anxiety, severity of symptoms, prolactin levels, and may represent a marker for impaired hormonal responses to stress. These findings should be considered when evaluating the discrepancies in DHEA studies in schizophrenia.

Several trials have indicated that selective serotonin reuptake inhibitors (SSRIs) are most efficient in the treatment of social phobia (SP). The activity of the serotonin transporter (5-HTT), as determined by [3H]5-HT uptake to blood lymphocytes, was measured in 15 drug-free patients with generalized SP (7M/8F, aged 21–37 years) and compared to 18 healthy control subjects (10M/8F, aged 21–32 years). The maximum uptake velocity (Vmax) of [3H]5-HT to fresh lymphocytes and the affinity (Km) of the 5-HTT were similar in the two groups (295 ± 155 versus 227 ± 117 pmol/min/mg protein and 767 ± 425 versus 709 ± 408 nM, respectively). This study suggests that the functioning of lymphocyte 5-HTT is unaltered in SP.

Nineteen female adolescent inpatients diagnosed with anorexia nervosa, restricting type (AN-R) and 16 non-eating disordered (ED) controls were assessed for plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulphate (DHEA-S), and cortisol levels, and for eating-related and non-eating-related psychopathology. AN-R patients were assessed at admission, 1 month and 4 months following hospitalization. The non-ED controls were assessed once. No baseline between-group differences were found in plasma cortisol, DHEA, and DHEA-S levels, whereas the patient group had a significantly lower Cortisol/DHEA-S ratio and elevated scores on most psychopathological parameters. A significant increase was found in the body mass index of the AN-R patients at 4 months post-hospitalization, accompanied by a decrease in plasma cortisol levels and a trend towards decreased Cortisol/DHEA and Cortisol/DHEA-S ratios, whereas no change occurred in psychopathology. The difference in Cortisol/DHEA-S ratio between AN-R patients and non-ED controls, and the different patterns of change in cortisol vs. DHEA(-S) levels following weight restoration, may in part account for the feeding difficulties in AN, particularly during refeeding.

Brain vesicular monoamine transporter 2 (VMAT2) has a critical role in the regulation of monoaminergic neurotransmission. In our previous study we have found decreased platelet VMAT2 density in healthy habitual smokers. Schizophrenia is associated with high rate of cigarette smoking. In the present study we assessed platelet VMAT2 pharmacodynamic characteristics in a population of medicated schizophrenia patients (n=36) comparing smokers (n=23) vs. non-smokers (n=13). A significant decrease in platelet VMAT2 density (24%, p=0.005) was found in the smokers compared to the non-smokers . This decrease was not ascribed to the pharmacotherapy. An inverse correlation was found in the smokers between the platelet VMAT2 density and the severity of schizophrenia as assessed by the positive and negative syndrome scale (PANSS). Our observation in schizophrenia patients is consistent with that found in healthy smokers. The complex relationship between VMAT2 expression, cigarette smoking and schizophrenia merits a further large scale study.

The aim of this study was to determine for the first time neurosteroid levels, dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in particular, in a group of adult patients with autistic disorder and compare these levels with normal healthy individuals. Levels of DHEA, DHEA-S and cortisol were compared between 15 adult drug-free patients with autistic disorder and 13 healthy controls. The Ritvo-Freeman Real-Life Rating Scale (RLRS) and the Overt Aggression Scale (OAS) were assessed as a measure of symptom severity. Significant lower DHEA-S levels were observed in the group with autistic disorder as compared to controls (p

The brain vesicular monoamine transporter (VMAT2) is part of the re-uptake mechanism which regulates monoaminergic neurotransmission. We demonstrated previously a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. Nicotine induced increase of dopamine and serotonin neurotransmission in limbic structures may alter the expression of VMAT2 in brains of smokers. In this study we measured the VMAT2 pharmacodynamic characteristics using high-affinity [3H]dihydrotetrabenazine (TBZOH) binding to platelets of smokers (n=15) compared to sex and age matched healthy nonsmokers controls (n=14). A significant decrease (17%, P=0.02) in VMAT2 density (Bmax) was observed in platelets of smokers compared to nonsmokers. There was no significant difference in the affinity of [3H]TBZOH to its platelet binding site and the VMAT2 density did not correlate with the heaviness of smoking. The decreased density of the VMAT2 in the platelets of smokers may reflect nicotine induced desensitization of VMAT2, a phenomenon that may be relevant to the addictive properties of nicotine.

The aim of the present study was to assess vesicular monoamine transporter (VMAT2) density in attention deficit/hyperactivity disorder (ADHD), a disorder involving monoaminergic dysregulation. It was hypothesized that the hypoactivity of monoaminergic neurotransmission related to ADHD could be associated with an under-expression of VMAT2. We assessed high affinity [3H]dihydrotetrabenazine [TBZOH] binding to platelet VMAT2 in untreated male ADHD children and adolescents (n=11) as compared to age-matched controls (n=14), as well as the correlation between VMAT2 density and the severity of ADHD symptoms as measured by the clinician-administered DSM-IV ADHD Scale (DAS) and the parent-administered Abbreviated Conners' Rating Scale (ACPRS). The [3H]TBZOH binding capacity (Bmax) was significantly lower (17%) in the ADHD group as compared to the controls. There was no difference between the two groups in the affinity (Kd value) of [3H]TBZOH to its binding site. An inverse correlation was found between the ADHD symptom scales and the Bmax values. It remains unclear whether the under-expression of platelet VMAT2 in ADHD children is reflective of a parallel change in the brain, and whether it is primary or an epiphenomenon of ADHD.

In continuation of our previous studies on orbitofrontal cortex function in obsessive compulsive disorder (OCD) we studied a group of OCD patients with schizophrenia in comparison with a group of schizophrenia patients. In order to test orbitofrontal cortex function we again used an alternation learning task. We found no difference between the two groups in the performance of this task. The relationship between severity of OC symptoms and alternation learning was curvilinear. Thus, in the low range of symptom severity the correlation between alternation learning and symptom severity was negative, while in the high range it was positive. The positive correlation in the severely affected patients is essentially the same as that found in severe "pure" OCD patients, which we have previously reported. We conclude that the data indicate independent orbitofrontal cortex function in OCD, irrespective of comorbidity.

Schizophrenia patients may exhibit altered body temperature. We hypothesized that drug-free patients may have a higher corneal temperature than normal subjects. The corneal temperature of seven remitted drug-free schizophrenia outpatients and seven healthy volunteers was evaluated with a flir thermal imaging camera. A significantly higher corneal temperature was observed in the patient group (34.60+/-1.89 vs. 33.05+/-0.58 degrees C; P=0.005) and it correlated with their BPRS score (r=0.82; P=0.024). The relevance of these preliminary findings merit further investigation.

Vesicular monoamine transporter (VMAT2) plays a major role in the synaptic accumulation and release of monoamines. In the present study, we assessed high affinity [(3)H]dihydrotetrabenazine binding to platelet VMAT2 in a group of treated (n = 9) and untreated (n = 4) patients with schizophrenia and age- and sex-matched controls. Significantly elevated platelet VMAT2 density (B(max)) (53%, P0.0001) was observed in the mixed population of schizophrenia patients. The affinity of the ligand (K(d)) to platelet VMAT2 was similar in both groups. The increased platelet VMAT2 density may indicate a schizophrenia-related hyperactivity of the monoaminergic system or an adaptive response to chronic drug treatment.

We compared the effect of chronic clozapine and haloperidol treatment on the expression of rat brain vesicular monoamine transporter (VMAT(2)) as well as on the membranal presynaptic transporters for serotonin, dopamine and noradrenaline. Rats were treated for 21 days with clozapine (25 mg/kg), haloperidol (0.5 mg/kg) or saline. VMAT(2) expression was assessed on the protein level by high affinity [3H]dihydrotetrabenazine binding using autoradiography, and on the mRNA level by in situ hybridization. The densities of the monoamine transporters were evaluated by autoradiography using specific ligands. Clozapine administration led to an increase in [3H]TBZOH binding in the nucleus accumbens, prefrontal cortex and striatum, whereas haloperidol had no effect on VMAT(2) binding capacity. The clozapine-induced increase in VMAT(2) was accompanied by a parallel increase in the membrane serotonin transporter in the prefrontal cortex and the striatum. Haloperidol induced an increase in the serotonin transporter in the striatum and the core of the nucleus accumbens. The special effect of clozapine on VMAT(2) expression may be relevant to its unique therapeutic advantages.

Schizophrenia patients may develop various thermoregulatory disturbances. We hypothesized that a standardized exercise-heat tolerance test [two 50-min bouts of walking a motor-driven treadmill at 40 degrees C (relative humidity=40%)] would reveal abnormal thermoregulation in drug-free schizophrenia patients. Six drug-free schizophrenia outpatients and seven healthy comparison subjects participated in this study. The schizophrenia patients exhibited significantly higher baseline and exertion-related rectal temperature. The relevance of these findings to the pathophysiology of schizophrenia-related thermoregulatory disorders is as yet unclear.

The hippocampus, a medial temporal lobe structure, is often considered to play an important role in the pathophysiology of schizophrenia. Recent developments of neuroimaging and molecular postmortem techniques have significantly increased our ability to study the role of discrete brain regions in the pathophysiology of schizophrenia. This article describes animal models, structural, histological, molecular biology, and neuropsychological evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. The major findings in schizophrenic patients are decreased volumes, hypometabolism, and cytoarchitectural abnormalities which are more robust on the left hippocampus, as well as verbal memory impairment. It is yet to be determined whether these changes are neurodevelopmental or neurodegenerative in nature. Overall, these findings indicate that there are subtle changes in the hippocampus of schizophrenic patients. More comprehensive and focused hippocampal research in schizophrenia is required to elucidate the contribution of this intriguing brain structure to the pathophysiology of schizophrenia.

Background : Actigraphy is a quantitative method for measurement of motor activity. In the present study we used actigraphy to examine diurnal variations in locomotor activity of schizophrenic patients with neuroleptic-induced akathisia (NIA). Method : Thirty-two schizophrenic patients, 16 with NIA and 16 without (DSM-IV criteria) underwent 24-h actigraphic monitoring. Clinical assessments of NIA were conducted with Barnes Akathisia Scale (BAS) at 08:00, 12:00, 16:00 and 20:00. Sleep parameters (duration, latency, continuity and efficacy) were assessed by actigraphy. Sleep quality was evaluated by a self-rated sleep questionnaire. Results : NIA patients demonstrated persistent higher daytime motor activity from 11:30 to 14:15 and from 18:00 to 21:00 than controls. There were no differences between the groups in nighttime motor activity, confirming clinical observations that NIA tends to disappear during sleep. Subject’s sleep assessments were similar in the two groups. Conclusions : Actigraphy seems to be a reliable, non-invasive, method of measuring motor activity in patients with NIA. Its sensitivity and specificity as an objective quantitative diagnostic instrument in patients with NIA merits further investigation.

Background: We have previously reported a significant negative correlation between severity of symptoms and performance of an alternation learning task in female obsessive–compulsive disorder (OCD) patients. The present study was aimed at exploring this relationship between alternation learning and OCD symptom severity in male OCD patients. Methods and results: Eighteen female obsessive–compulsive disorder patients and 14 male non-depressed, drug free, OCD patients participated in the study. Measures of dorsolateral prefrontal function (Wisconsin Card Sorting Test) and orbitofrontal cortex function (object alternation learning) showed no significant differences between the sexes. The relationship between orbitofrontal cortex function and severity of OC symptoms was significantly different between the sexes (z=2.44, P=0.007). While this correlation was negative in the females it was positive in the males. Conclusions: These results may indicate sexual dimorphism in OCD.

Background: Olfactory quality discrimination is a putative marker of orbitofrontal cortex function in mammals. As this portion of the cerebral cortex was repeatedly implicated in the pathophysiology of obsessive-compulsive disorder (OCD) this study was designed in an attempt to quantify this behavioural function in OCD patients. Methods and Results: Olfactory quality discrimination was compared in OCD patients and healthy controls. Thirty two subjects participated in the study: 16 (13 women and 3 men) medication free OCD outpatients and 16 sex and age matched healthy controls. Olfactory tests consisted of determination of detection thresholds to isoamyl acetate, and a three way forced choice quality discrimination task, using isoamyl acetate, citral and eugenol as stimuli. No significant differences in sensitivity and performance of the quality discrimination task between the two groups were found. Within the OCD group the more severely affected patients (Y-BOCS>29) performed significantly better than the less severely affected (Y-BOCS

Overall Abstract 22q11 deletion syndrome (22q11DS), also known as velo-cardio-facial syndrome has been the focus of intensive research over the last 15 years. The syndrome is the most commonly known microdeletion syndrome, occurring in at least 1 to 4,000 live births, and is the most commonly known genetic syndrome associated with schizophrenia, with approximately one-thirds of individuals developing schizophrenia by young adulthood. Thus, 22q11DS provides a homogeneous model from which to learn about the effects of decreased dosage of genes on the development of brain structure and function and consequently on the emergence of schizophrenia-like psychotic disorder. The proposed symposium consists of leading 22q11DS international researchers and clinicians and young Israeli scientists. The presenters study longitudinally large cohorts of children, adolescents and young adults with 22q11.2DS. Dr. Gothelf will provide an introduction on the genetic and medical characteristics of 22q11DS. He will also present data on the genotype-neuropsychiatric phenotype associations in 22q11DS and preliminary findings of elevated levels of neuroinflammatory factors in psychotic 22q11DS individuals. Dr. Gur will describe the common psychiatric comorbidities occurring in two-thirds of individuals with 22q11DS including ADHD, anxiety disorders and psychotic disorders. She will also present longitudinal data following the developmental trajectories of attenuated psychotic symptoms in 22q11DS. Dr. Kates will summarize a twelve-year longitudinal study of neuroanatomic, neurofunctional and neuropsychological development in youth with 22q11.2 deletion syndrome (22q11DS). Dr. Kates identified aberrant longitudinal alterations in cortical thickness / connectivity, as well as neurocognitive deficits that may represent biomarkers for the eventual onset of prodromal psychosis in 22q11DS. Finally Dr. Michaelovsky will present the results of bioinformatics analyses on DNA samples of a unique 22q11.2DS multigeneration family (mother and her four children), including psychotic and non-psychotic subjects.

We examined the influence of the atypical antipsychotic agent clozapine compared to haloperidol, on levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate ester (both γ-aminobutyric acid A (GABA A ) receptor allosteric antagonists) in the rat cortex. i.p. injections of clozapine (5 and 15 mg/kg), but not haloperidol (1 mg/kg), for 8 days decreased rat brain cortical dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. These findings support the role of neurosteroids and possibly GABA A receptor modulation in the mechanism of action of clozapine.

We examined, in a controlled design, potential alterations in body temperature of male schizophrenic patients following acute antipsychotic drug (APD) administration. Fourteen drug-free (study group) and seven schizophrenic patients maintained on APDs (comparison group) initiated or received higher dose of their APD, respectively, for 27 days. Initial body temperature was 0.36 degrees C higher in the study group (P=0.01) and decreased within 24 h to values comparable to that of the comparison group (all within normal range).

B.H. Amit1 °, A. Krivoy1, I. Mansbach-Kleinfeld2, G. Zalsman3, A.M. Ponizovsky2, M. Hoshen4, I. Farbstein5, A. Apter6, A. Weizman1, G. Shoval3 1Geha Mental Health Center, Research Unit, Petah Tikva, Israel; 2Ministry of Health, Mental Health Services, Jerusalem, Israel; 3Geha Mental Health Center, Child and Adolescent Division, Petah Tikva, Israel; 4Clalit Health Services, Research Institute, Tel Aviv, Israel; 5Ziv Medical Center, Child and Adolescent Psychiatry, Safed, Israel; 6Schneider Children’s Medical Center, Outpatient clinics, Petah Tikva, Israel