Effect of Clozapine and Other Antipsychotics on the Level of Platelet-Associated Autoantibodies in Children with Schizophrenia: A Longitudinal Follow-Up Study.

BACKGROUND: Previous studies have demonstrated significantly higher blood titers of platelet-associated autoantibodies (PAA) in adult schizophrenia patients compared to normal healthy subjects. In addition, young adult schizophrenia patients at their early stages of the disorder displayed higher PAA titers than older patients with longer duration of the disorder. AIM: To assess longitudinally the blood titers of PAA in inpatients with childhood-onset schizophrenia at admission, after short- and long-term follow-up, and the correlation of these titers with the response to clozapine and other antipsychotic treatments. METHODS: Thirty children, age range of 6-12 (mean ± SD: 9.6 ± 1.5 years), with DSM-IV TR schizophrenia in active psychotic state were assessed 3 times: at baseline, after short-term (8-17 weeks; n = 26) and after long-term follow-up (33-170 weeks; n = 19). The blood titers of PAA were analyzed using ELISA and expressed by a linear optical density (OD) scale. A test recording >1.4 OD units was predefined as the positive cutoff value. RESULTS: On long-term follow-up, 9 out of the 17 children who were PAA-positive at baseline became PAA-negative: 7 already after 2 months of clozapine treatment and 2 following 3 years of risperidone treatment. Eight children remained PAA-positive during the entire study period. There was no significant correlation between the clinical improvement (as assessed by change in the Positive and Negative Syndrome Scale score) and the alteration in PAA levels (n = 19, r = -0.4, p = 0.088). CONCLUSIONS: High rates of positive PAA in COS patients may indicate an active autoimmune process in early-onset schizophrenia. It is concluded that PAA may serve as a biomarker for the diagnosis of COS, but does not predict the response to treatment. A transition to a PAA-negative status does not indicate an improvement in psychosis. © 2015 S. Karger AG, Basel.

Childhood adversity moderates the effect of ADH1B on risk for alcohol-related phenotypes in Jewish Israeli drinkers.

Childhood adversity and genetic variant ADH1B-rs1229984 have each been shown to influence heavy alcohol consumption and disorders. However, little is known about how these factors jointly influence these outcomes. We assessed the main and additive interactive effects of childhood adversity (abuse, neglect and parental divorce) and the ADH1B-rs1229984 on the quantitative phenotypes 'maximum drinks in a day' (Maxdrinks) and DSM-Alcohol Use Disorder (AUD) severity, adjusting for demographic variables, in an Israeli sample of adult household residents (n = 1143) evaluated between 2007 and 2009. Childhood adversity and absence of the protective ADH1B-rs1229984 A allele were associated with greater mean Maxdrinks (mean differences: 1.50; 1.13, respectively) and AUD severity (mean ratios: 0.71; 0.27, respectively). In addition, childhood adversity moderated the ADH1B-rs1229984 effect on Maxdrinks (P < 0.01) and AUD severity (P < 0.05), in that there was a stronger effect of ADH1B-rs1229984 genotype on Maxdrinks and AUD severity among those who had experienced childhood adversity compared with those who had not. ADH1B-rs1229984 impacts alcohol metabolism. Therefore, among those at risk for greater consumption, e.g. those who experienced childhood adversity, ADH1B-rs1229984 appears to have a stronger effect on alcohol consumption and consequently on risk for AUD symptom severity. Evidence for the interaction of genetic vulnerability and early life adversity on alcohol-related phenotypes provides further insight into the complex relationships between genetic and environmental risk factors.

Alcohol dependence and suicide-related ideation/behaviors in an Israeli household sample, with and without major depression.

BACKGROUND: Suicide-related ideation and behaviors (SRIB) are associated with both alcohol disorders and major depressive disorder (MDD). The objective of this study was to evaluate the relationship of alcohol dependence (AD) and major depression to the risk for lifetime SRIB. METHODS: Data from a community-based sample of 1,237 adult Israeli lifetime drinkers assessed with reliable diagnostic measures were analyzed using logistic regression. RESULTS: Lifetime SRIB was reported in 4.7% and was more prevalent among participants with AD (9.0%) than among those without AD (4.1%); p-value = 0.01. Although both AD and major depression were associated with SRIB (AD: OR 2.2, 95% CI 1.1 to 4.4; MDD: OR 11.4, 95% CI = 6.4 to 20.4), joint analysis showed that AD without MDD increased risk for SRIB as compared to those without AD or MDD (OR 3.1, 95% CI 1.1 to 9.1), but AD did not increase risk among those with MDD (OR 1.1, 95% CI 0.4 to 2.7). Among those with AD, the severity of subclinical depressive symptoms was associated with increased SRIB. CONCLUSIONS: These findings show that AD increases risk for SRIB among individuals without a history of major depression. Suicidal tendencies may be undetected and underdiagnosed in this group because of the absence of major depression and therefore left untreated. These findings should be considered when adopting suicide prevention or treatment strategies for this high-risk subpopulation.

Trauma exposure, posttraumatic stress disorder and risk for alcohol, nicotine, and marijuana dependence in Israel.

BACKGROUND: Substance dependence is more common among trauma-exposed individuals; however, most studies suggest that Posttraumatic Stress Disorder (PTSD) accounts for the link between trauma exposure (TE) and substance dependence. OBJECTIVES: This study examined associations between TE and substance dependence (alcohol, nicotine, and marijuana), and whether PTSD accounted for this association. METHOD: 1317 Jewish Israeli household residents completed in-person structured interviews assessing TE, PTSD, and substance (alcohol, nicotine, marijuana) dependence between 2007 and 2009. Regression analyses examined associations among TE, PTSD, and substance dependence. RESULTS: In the full sample, mean number of traumatic events was 2.7 (sd=2.2), with 83.7% experiencing at least one event. In the full sample, mean number of PTSD symptoms was 2.5 (sd=3.4), with 13.5% meeting PTSD diagnostic criteria. Prevalence of alcohol dependence was 13.4%; nicotine dependence 52.8%; and marijuana dependence 12.1%. Number of traumatic events was associated with increased odds of alcohol (OR=1.3; 95% CI=1.2-1.4) and nicotine (OR=1.2; 95% CI=1.1-1.3) dependence. Similarly, any traumatic event exposure was associated with increased odds of alcohol (OR=3.1; 95% CI=1.6-6.0) and nicotine (OR=1.9; 95% CI=1.2-2.9) dependence. PTSD symptoms were associated with increased odds of alcohol (OR=1.2; 95% CI=1.1-1.3), nicotine (OR=1.1; 95% CI=1.1-1.2), and marijuana (OR=1.1; 95% CI=1.04-1.2) dependence; similarly, a PTSD diagnosis was associated with increased odds of alcohol (OR=3.4; 95% CI=2.1-5.5), nicotine (OR=2.2; 95% CI=1.4-3.4), and marijuana (OR=2.6; 95% CI=1.2-5.9) dependence. PTSD symptoms accounted for a sizeable proportion of the TE effect on alcohol (46%) and nicotine dependence (31%). CONCLUSION: Individuals with more traumatic events had heightened risk for alcohol and nicotine dependence, and PTSD symptoms partially accounted for this risk. However, marijuana dependence was only significantly related to PTSD symptoms. Clinicians and researchers should separately assess different types of dependence among trauma-exposed individuals both with and without PTSD symptoms.

Alcohol-metabolizing genes and alcohol phenotypes in an Israeli household sample.

BACKGROUND: Alcohol dehydrogenase 1B and 1C (ADH1B and ADH1C) variants have been robustly associated with alcohol phenotypes in East Asian populations, but less so in non-Asian populations where prevalence of the most protective ADH1B allele is low (generally <5%). Further, the joint effects of ADH1B and ADH1C on alcohol phenotypes have been unclear. Therefore, we tested the independent and joint effects of ADH1B and ADH1C on alcohol phenotypes in an Israeli sample, with higher prevalence of the most protective ADH1B allele than other non-Asian populations. METHODS: A structured interview assessed lifetime drinking and alcohol use disorders (AUDs) in adult Israeli household residents. Four single nucleotide polymorphisms (SNPs) were genotyped: ADH1B (rs1229984, rs1229982, and rs1159918) and ADH1C (rs698). Regression analysis examined the association between alcohol phenotypes and each SNP (absence vs. presence of the protective allele) as well as rs698/rs1229984 diplotypes (also indicating absence or presence of protective alleles) in lifetime drinkers (n = 1,129). RESULTS: Lack of the ADH1B rs1229984 protective allele was significantly associated with consumption- and AUD-related phenotypes (OR = 1.77 for AUD; OR = 1.83 for risk drinking), while lack of the ADH1C rs698 protective allele was significantly associated with AUD-related phenotypes (OR = 2.32 for AUD). Diplotype analysis indicated that jointly ADH1B and ADH1C significantly influenced AUD-related phenotypes. For example, among those without protective alleles for ADH1B or ADH1C, OR for AUD was 1.87 as compared to those without the protective allele for ADH1B only and was 3.16 as compared to those with protective alleles for both ADH1B and ADH1C. CONCLUSIONS: This study adds support for the relationship of ADH1B and ADH1C and alcohol phenotypes in non-Asians. Further, these findings help clarify the mixed results from previous studies by showing that ADH1B and ADH1C jointly effect AUDs, but not consumption. Studies of the association between alcohol phenotypes and either ADH1B or ADH1C alone may employ an oversimplified model, masking relevant information.

High circulatory titer of platelet-associated autoantibodies in childhood onset schizophrenia and its diagnostic implications.

BACKGROUND: It has been suggested that the etiology of schizophrenia, in a distinct group of patients, originates from an autoimmune reaction against platelets. Previous studies have demonstrated significantly higher blood titers of platelet-associated autoantibodies (PAA) in adult schizophrenia patients as compared to normal healthy subjects. In addition, young adult schizophrenia patients at their early stages of the disorder displayed higher PAA titers than older patients with longer duration of the disorder. AIM: To assess the blood titers of PAA in children with schizophrenia as compared to matched control subjects without psychotic disorders, as a possible diagnostic parameter. METHODS: Twenty-nine children with DSM-IV schizophrenia in the active psychotic state, with an age range of 6-12 years (mean ± SD: 9.6 ± 1.5 years), with average Positive and Negative Syndrome Scale scores of 108 ± 19.2, were assessed. The control group consisted of 25 children with DSM-IV conduct disorder in a similar age range of 5-12 years (mean ± SD: 9.5 ± 1.6 years). The blood titers of PAA were evaluated using an optimized ELISA test, expressed by a linear optical density (OD) scale. The blood samples of all participants were tested anonymously and were scored under a code number. A test recording above 1.4 OD units was predefined as positive. RESULTS: The titers of PAA of children with schizophrenia (1.9 ± 0.5 OD units, range: 0.7-2.44 units) were significantly (p < 0.00001) higher than those of the control group (1.0 ± 0.4 OD units, range: 0.45-2.28 units). In 83% of the children with schizophrenia (24 out of the 29 patients) a positive test, i.e. OD >1.4, was detected. In contrast, in the control group, only 12% (3 of the 25 subjects) displayed a positive test, p < 0.00001. CONCLUSIONS: High titers of PAA in children with schizophrenia as compared with nonpsychotic controls may indicate an active autoimmune process in the early onset of schizophrenia. The PAA level may therefore provide a supportive diagnostic biomarker for childhood schizophrenia.

Over-Reporting of Somatic and Psychiatric PTSD Symptoms Among People Who Experienced Motor Vehicle Accidents and Did Not Seek Psychiatric Help in a Primary Care Setting.

Background: Over-reporting of posttraumatic stress disorder (PTSD) symptoms has been observed in some cases, following a motor vehicle accident (MVA). It has been suggested, however, that these are cases of underdiagnoses in primary care settings. The current study focused on people with PTSD in primary care settings who experienced an MVA and do not seek psychiatric help. Methods: In the over 3000 patient registry of a primary care clinic, 174 people who experienced an MVA (PE-MVA) were identified. The final sample included 45 PE-MVA, who were administered the Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS-2), and completed the Injury Severity Scale (ISS) and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) content scales. Results: PE-MVA with PTSD reported more psychopathology on both MMPI-2 and CAPS-2 than those without PTSD. Severity of injury, measured by the ISS, did not differ significantly between the two PE-MVA groups. The significant differences between the PE-MVA with PTSD and those without PTSD disappeared after adjusting for the covariates of bias scales [Infrequency (F) and Fake Bad (FBS)] in MMPI-2, but not in CAPS-2. Conclusion: The results suggest that in primary care settings, PE-MVA with PTSD who do not seek psychiatric help, over-report psychiatric and somatic symptoms. In a personal injury setting the F scale of the MMPI-2 showed less sensitivity to exaggerated somatic symptoms than the FBS scale. Bias scales of PE-MVA with PTSD are major contributors to the elevation of the MMPI-2 scores but not the CAPS-2 score.

Identification of population substructure among Jews using STR markers and dependence on reference populations included.

BACKGROUND: Detecting population substructure is a critical issue for association studies of health behaviors and other traits. Whether inherent in the population or an artifact of marker choice, determining aspects of a population's genetic history as potential sources of substructure can aid in design of future genetic studies. Jewish populations, among which association studies are often conducted, have a known history of migrations. As a necessary step in understanding population structure to conduct valid association studies of health behaviors among Israeli Jews, we investigated genetic signatures of this history and quantified substructure to facilitate future investigations of these phenotypes in this population. RESULTS: Using 32 autosomal STR markers and the program STRUCTURE, we differentiated between Ashkenazi (AJ, N = 135) and non-Ashkenazi (NAJ, N = 226) Jewish populations in the form of Northern and Southern geographic genetic components (AJ north 73%, south 23%, NAJ north 33%, south 60%). The ability to detect substructure within these closely related populations using a small STR panel was contingent on including additional samples representing major continental populations in the analyses. CONCLUSIONS: Although clustering programs such as STRUCTURE are designed to assign proportions of ancestry to individuals without reference population information, when Jewish samples were analyzed in the absence of proxy parental populations, substructure within Jews was not detected. Generally, for samples with a given grandparental country of birth, STRUCTURE assignment values to Northern, Southern, African and Asian clusters agreed with mitochondrial DNA and Y-chromosomal data from previous studies as well as historical records of migration and intermarriage.

Blind verification of elevated platelet autoantibodies in serum of schizophrenic patients--part II: adult subjects.

BACKGROUND: In our preceding study, we assayed in a blind fashion the blood sera of young normal subjects and schizophrenic patients for levels of platelet autoantibodies (PAA). The recorded PAA titers of the schizophrenic patients were significantly higher than those of the normal subjects. This observation has lent support to this test being used as an objective evaluation of schizophrenia in young subjects in the future. In addition, this finding strongly suggested that the etiology of a distinct group of sufferers of this disorder could have originated from an autoimmune reaction against platelets which can, under certain conditions, cross-react with brain tissue. AIMS: In the present study, PAA titers in the sera of adult schizophrenic patients and matched normal subjects were determined analogously to the preceding study. The effect of hospitalization and drug treatments on the apparent blood test scoring in adult subjects could thus be evaluated. METHODS: A total of 46 schizophrenia patients (30 men and 16 women) aged 19-45 years (mean +/- SD: 31.7 +/- 8.0 years) with a minimum score of 60 on the Positive and Negative Symptom Scale and 43 healthy control subjects (22 men and 21 women) aged 21-44 years (mean +/- SD: 31.9 +/- 6.9 years) participated in the study. The blood titers of PAA were evaluated in a single-blind fashion using an optimized ELISA test scored by optical density (OD) units. A positive test was defined as a value above 1.3 OD units. RESULTS: The titers of PAA in the group of schizophrenic patients (1.1 +/- 0.55 OD units, range: 0.360-2.285 OD units) were significantly higher in comparison to those of the healthy control subjects (0.81 +/- 0.37 OD units, range: 0.360-1.704 OD units; p = 0.004, two-tailed unpaired t-test). Significantly more schizophrenic patients showed a positive test (15 patients out of 46) than the control subjects (5 out of 43). However, significantly higher OD values of 1.55 +/- 0.5 were recorded in the group of patients with less than 3 years of registered disease (n = 16, age 19-30 years), while in the group with 4-20 years of hospitalization (n = 30, age 24-45 years) the recorded OD values (0.85 +/- 0.4 OD units) were practically indistinguishable from those of the control group. CONCLUSIONS: In the adult schizophrenic patients, the PAA blood test remains valid for patients who were hospitalized for less than 3 years. Drug treatment, length of disease and age can be assumed to reduce the PAA level considerably.

Blind verification of elevated platelet autoantibodies in serum of schizophrenic patients--part I: young subjects.

BACKGROUND: It has been hypothesized that the etiology of schizophrenia, in a distinct group of patients, originates from an autoimmune reaction against platelets. Previous open screenings have recorded significantly higher blood titers of platelet-associated autoantibodies (PAA) in schizophrenic patients as compared to normal healthy subjects. In addition, young schizophrenic patients at the early stages of their disorder displayed higher PAA titers than older patients with a longer duration of the disorder. A blood test based on these observations was proposed. AIM: To verify by a blind test a significant difference in PAA between young schizophrenic patients and matched healthy control subjects, for the validation of a blood test for schizophrenia. METHODS: A total of 36 young schizophrenic patients in an active psychotic state, aged 13-20 years (mean +/- SD: 16.2 +/- 2.1 years) with an average PANSS score of 115.6 +/- 14.5 and illness duration of 9.5 +/- 9.4 months, were examined. The control group consisted of 49 healthy young subjects between the ages of 13 and 21 years (16.2 +/- 2.2 years). The blood titers of PAA were evaluated blindly using an optimized ELISA test, expressed by a linear optical density (OD) scale. The blood samples of all participants were tested anonymously, and were scored under a code number. A test recording above 1.3 OD units was defined as positive. RESULTS: The PAA titers of schizophrenia patients (1.6 +/- 0.4 OD units, range: 0.7-2.3 OD units) were significantly higher than those of the control group (1.0 +/- 0.4 OD units, range: 0.4-1.8 OD units; p < 0.0001). In 61% of the young schizophrenic patients (22 out of the 36 patients), a positive result (OD >1.3 units) was recorded. In the control group, only 12.2% (6 of the 49 subjects) displayed a positive result (p < 0.0001). CONCLUSIONS: These findings support further assessment of PAA titers as a potential biomarker for patients with clinical signs and symptoms of schizophrenia.

The effectiveness of high-dose escitalopram in the treatment of patients suffering from schizophrenia with comorbid obsessive-compulsive disorder: an open-label study.

Obsessive-compulsive disorder frequently co-occur with schizophrenia causing a significant impairment. There is a paucity of published data on the treatment of such complicated patients. It has been suggested that the combination of antipsychotics and antiobsessive agents is the best treatment for schizophrenia with obsessive-compulsive disorder; however, there is no published data regarding the use of high dose (up to 40 mg/day) escitalopram. This open-label, prospective study was designed to investigate the efficacy, short-term safety and tolerability of escitalopram in doses up to 40 mg in patients with schizophrenia and obsessive-compulsive disorder. Patients were treated with increasing doses of escitalopram for 13 weeks. Thirteen patients (86.67%) completed the study. A significant improvement was observed in the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores and in the scores of Y-BOCS-Obsession and Y-BOCS-Compulsion subscales. Furthermore, a significant improvement was observed in the total scores of the Positive and Negative Syndrome Scale and Clinical Global Impression-severity scale. Escitalopram, up to 40 mg/day was well tolerated and may be beneficial in the management of patients with schizophrenia and obsessive-compulsive disorder. Further studies are needed to confirm this finding and to assess long-term safety.

Elevated serum homocysteine levels in male patients with PTSD.

It has been suggested that an elevated serum or plasma homocysteine level may be a risk factor for neuropsychiatric conditions such as Alzheimer's disease, schizophrenia, and depression. Because depression is closely related to anxiety disorders, and because it has been suggested that stress may be associated with an elevated homocysteine level, we studied whether serum homocysteine levels are elevated in patients with posttraumatic stress disorder (PTSD). Total serum homocysteine levels in 28 male patients with PTSD were compared to those of 223 healthy controls. The effect of PTSD on the serum homocysteine level was significant (F=42.96, P<.0001). In a regression model for the PTSD patients, the duration of PTSD was found to predict serum homocysteine levels (t=2.228, P=.035). Our results suggest that elevated levels of homocysteine in male patients with PTSD may be related to pathophysiological aspects associated with the chronicity of this disorder.

An open-label randomized comparison of olanzapine versus risperidone in the treatment of childhood-onset schizophrenia.

BACKGROUND AND PURPOSE: Childhood-onset schizophrenia (COS) is a clinically severe form of schizophrenia, which causes severe impairment to cognitive, linguistic, and social development. There are few prospective and retrospective open clinical trials of risperidone and olanzapine in COS. In this open-label, randomized, prospective study, we compared the tolerability and effectiveness of risperidone versus olanzapine in the treatment of COS patients. METHODS: The study population consisted of 25 children with COS (mean age 11.09 +/- 1.55 years). After an evaluation, patients received risperidone (0.25-4.5 mg/day, mean dose 1.62 +/- 1.02 mg/day) or olanzapine (2.5-20 mg/day, mean dose 8.18 +/- 4.41 mg/day) for 12 weeks, with weekly evaluations. RESULTS: Both groups showed comparable significant (p < 0.001) within-group improvement from baseline to endpoint (LOCF) in Positive and Negative Symptoms Scale (PANSS) total and subscale scores. Of the olanzapine-treated children, 11 (91.7%) completed the 12 weeks of the study, whereas in the risperidone-treated children only 9 (69.2%) did. No significant differences between risperidone-treated children and olanzapine-treated children were observed on Barnes Akathisia Rating Scale (BAS) and Simpson-Angus Scale (SAS) rating scales. Both treatment groups showed significant (p < 0.001) increase in weight from baseline to endpoint. CONCLUSION: Our open-label, small-scale comparative study suggests that both risperidone and olanzapine appear to be efficacious antipsychotic medications in COS, with a slight nonsignificant advantage of olanzapine in the dropout rate.

CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.

OBJECTIVE: Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. METHOD: The associations between CHRNA5-CHRNA3-CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. RESULTS: At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p = .0025), more cigarettes smoked (p = .0057), and higher scores on the FTND (p =.0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p = .0026) and on FTND score (p = .0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. CONCLUSIONS: These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target.

Lowered DHEA-S plasma levels in adult individuals with autistic disorder.

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 < 0.05). DHEA-S levels appear to be low in patients with autistic disorder and, while speculative, may play a role in the etiopathophysiology of the disorder.

The effects of clozapine versus haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: an open, nonrandomized, 6-month study.

BACKGROUND: The risk of suicide for schizophrenia patients is 20 to 50 times higher than that for the general population. Long-term treatment with clozapine, an atypical antipsychotic, has been shown to reduce the rate of suicide by 80% to 85%. The goal of the present study was to examine whether clozapine's effect on the reduction of suicidal behavior in chronic schizophrenic patients could be due to a reduction in impulsive-aggressive behavior. METHOD: 44 patients with chronic DSM-IV schizophrenia were treated with clozapine or haloperidol decanoate in an open prospective 6-month trial. Changes in measures of suicidality, impulsiveness, aggression, depressed mood, and positive and negative symptoms were assessed at baseline and at 6 months. RESULTS: The clozapine-treated group (N = 18) had a significantly greater reduction on all outcome measures compared with the haloperidol decanoate-treated group (N = 26). Only in the clozapine-treated group did the reduction in measures of suicidality correlate significantly with a reduction in impulsiveness and aggression. The reductions in suicidality and impulsive aggression were not significantly correlated with reductions in depressed mood or positive and negative symptom scores in either group. CONCLUSION: These data suggest that the reduction in suicidality following long-term clozapine treatment may be related to a reduction in impulsiveness and aggression.

Brain neurosteroid changes after paroxetine administration in mice.

Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine.

Sulpiride augmentation of olanzapine in the management of treatment-resistant chronic schizophrenia: evidence for improvement of mood symptomatology.

Several recent studies, albeit limited in sample number, design and generalizability, have suggested that augmentation of atypical antipsychotic medication (such as clozapine and olanzapine) with sulpiride, a substituted benzamide antipsychotic medication, may play a role in the management of treatment-resistant psychotic conditions. The objective of this study was to investigate any change in clinical symptomatology or side-effect profile in treatment-resistant schizophrenia patients receiving sulpiride in addition to olanzapine. Seventeen patients with treatment-resistant chronic schizophrenia, who were receiving olanzapine monotherapy for at least 6 months before study commencement, were randomized in a 1:1 fashion to receive either adjunctive treatment with sulpiride (study group) or to continue their pre-study treatment with olanzapine with no medication augmentation (control group), each for a period of 8 weeks. Changes in measures of positive and negative symptoms, anxiety, depression and extrapyramidal symptoms were assessed at baseline and at 8 weeks. Study observations indicated no significant differences in the changes in positive or negative symptomatology between patients receiving a combined regimen of olanzapine with sulpiride (600 mg/ day) augmentation and controls. However, a significantly greater improvement of depressive symptomatology (P < 0.05; as assessed by the Hamilton Scale for Depression) was noted in the sulpiride augmentation group. These data indicate improvement in depressive symptomatology with sulpiride augmentation of olanzapine in treatment-resistant chronic schizophrenia patients.

Olanzapine treatment in chronic drug-resistant childhood-onset schizophrenia: an open-label study.

The use of typical antipsychotics is limited in children with schizophrenia, owing to the high rate of response failure and early appearance of extrapyramidal syndromes as well as tardive and withdrawal dyskinesia. The aim of the present study was to examine the effectiveness of the atypical antipsychotic olanzapine in the treatment of childhood-onset schizophrenia. The study sample included nine children hospitalized for schizophrenia who had proven refractory to treatment with at least two antipsychotic drugs. Olanzapine was administered after a 2-week washout period in gradually increasing doses to a maximum of 5 mg/day on day 5 and 10 mg/day in week 3; six patients received up to 20 mg/day as of week 5. The duration of the study was 12 weeks. Patient psychiatric status was measured with three scales at onset of therapy and thereafter once weekly. Patients also underwent regular blood, laboratory, and liver function tests, and we also monitored their blood pressure and weight and performed electrocardiography and electroencephalography. A reduction in all psychopathology scores was obtained at 12 weeks from baseline. All extrapyramidal symptoms of previous medications resolved, and there were no new incidents. Side effects were mild. There were no adverse changes in blood chemistry, hematological tests, or electrocardiography parameters, but the treatment was associated with a significant weight gain (6.10 +/- 3.25 kg). At 1-year follow-up, the improvement in psychiatric symptoms was sustained in eight children. We conclude that olanzapine may have potential as a first-line drug in the treatment of drug-resistant childhood-onset schizophrenia. Large-scale, double-blind, placebo-controlled comparative studies are needed to clarify the role of the various atypical antipsychotics in both treatment-resistant and treatment-naïve populations with psychotic symptoms/disorders.