HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

[Antisocial personality disorder]. / Epäsosiaalinen persoonallisuushäiriö.

Antisocial personality disorder (ASP), especially psychopathy as its extreme form, has provoked fear and excitement over thousands of years. Ruthless violence involved in the disorder has inspired scientists, too.The abundance of research results concerning epidemiology, physiology, neuroanatomy, heritability, and treatment interventions has made ASP one of the best documented disorders in psychiatry. Numerous interventions have been tested, but there is no current treatment algorithm. Biological and sociological parameters indicate the importance of early targeted interventions among the high risk children. Otherwise, as adults they cause the greatest harm. The use of medications or psychotherapy for adults needs careful consideration.

[Managing aggression and violence associated with psychosis]. / Psykoottisen potilaan aggressio--ehkaisy ja hoito.

Risk for violence in psychosis is associated with the subject's history of early-onset antisocial behavior, substance abuse, suicidal ideation, lack of insight, and non-adherence to antipsychotic medication. These risk factors can be managed by effective treatment for psychosis, with the exception of predatory antisocial aggression. Generally, this group of patients is at considerable risk for untreated conditions. There is, however, no pharmacological treatment indicated solely for aggression. Physical violence can often be avoided by alertness and risk monitoring, and by attentive customer service skills. Safety at work is our shared responsibility.

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.

Antipsychotic Polypharmacy in Clozapine Resistant Schizophrenia: A Randomized Controlled Trial of Tapering Antipsychotic Co-treatment.

There is a considerable disparity between clinical practice and recommendations based on meta-analyses of antipsychotic polypharmacy in clozapine resistant schizophrenia. For this reason, we investigated the clinical response to reducing the use olanzapine that had been previously added on clozapine treatment among seriously ill hospitalized patients. In a randomized controlled trial with crossover design, we studied volunteer patients (N=15) who had olanzapine added on to clozapine in a state mental hospital. Clozapine monotherapy was just as effective as clozapine-olanzapine therapy, according to results from Clinical Global Impression Scale and Global Assessment of Functioning as primary outcome measures. Polypharmacy is widely used in treating schizophrenia, and usually, add-on medications are started because of worsening of the clinical state. A major confounding feature of these add-ons is whether observed improvements are caused by the medication or explained by the natural fluctuating course of the disorder. The present study, in spite of its small size, indicates the necessity of reconsidering the value of polypharmacy in treating schizophrenia.

Costs of intensive psychiatric care for treatment-resistant minors.

BACKGROUND: Mental health problems in childhood and adolescence result in high costs to society. Despite the relevance of these problems, there are still relatively few economic evaluations of this domain, in particular the evaluation of the costs of treatment-resistant minors. AIM OF THE STUDY: The study is aimed to evaluate the costs of mental services use of 52 treatment-resistant minors at the Intensive Psychiatric Care Unit of the Niuvanniemi Hospital, in Kupio, Finland, and the costs of the mental health services used by these patients before their referral to this unit. METHODS: The data were collected from case history files of minors (N 2dd = 2dd 52) who were directed to the intensive psychiatric care unit between 2004 and 2007. The data included information of the use of earlier specialised medical psychiatric care. The study evaluated the cost of daily bed charges for treatment-resistant minors. RESULTS: The mean duration of the intensive psychiatric care unit treatment was twelve months. The average cost was 367,150/patient. Fifty-one per cent of the minors were discharged to less intensive mental health services after the intensive psychiatric care. CONCLUSIONS: The costs of intensive psychiatric treatment are currently high. Benefits may be achieved over time. Further research should monitor and analyse the benefit of such expensive treatment on the outcomes of treatment-resistant patients over time, an investment in the minors' future, that ultimately benefits society.

Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication. METHOD: Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003. RESULTS: In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms. CONCLUSION: Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.

Effects of venlafaxine treatment on clozapine plasma levels in schizophrenic patients.

Depressive symptoms are found at any stage of schizophrenia, and antidepressant medication may be beneficial. Selective serotonin reuptake inhibitor antidepressants have been considered safe in schizophrenia but in combination with clozapine, that is widely used in chronic treatment-resistant schizophrenia, remarkable pharmacokinetic interactions can occur causing an elevation in clozapine plasma levels. To investigate this further, the plasma levels of clozapine were measured in 11 schizophrenic male patients with depressive symptoms who were administered both clozapine and venlafaxine. Low to moderate doses of venlafaxine did not seem to have any significant effect on clozapine plasma levels.

Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial.

BACKGROUND: There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine. METHODS: Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period. RESULTS: In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms. CONCLUSIONS: These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.

Ethanol consumption and DRD2 gene TaqI a polymorphism among socially drinking males.

The dopaminergic system in the human brain is thought to play a major role in the development of alcohol consumption habits and alcoholism. It has been reported that homozygous D2-/- knock-out mice lacking D2 receptors consume about 50% to 60% less ethanol than wild-type D2+/+ mice, and heterozygous mice have an intermediate level of alcohol consumption. The DRD2 gene TaqI A polymorphism has been suggested to associate with a low D2 receptor density in post mortem and in vivo measurements. Numerous association studies on this polymorphism and alcoholism have shown most controversial results. We studied whether DRD2 TaqI A genotype affects alcohol consumption in an ethnically homogeneous, representative sample of 1,019 Finnish Caucasian males. After excluding the abstainers from the study, the self-reported alcohol consumption among the remaining 884 non-abstainers was compared in the TaqI A genotype groups (A1/A1, A1/A2, A2/A2). The alcohol consumption of the homozygous A1/A1 group was about 30% lower than in A1/A2 group, and 40% lower than in A2/A2 group (P = 0.042 and 0.041 in a sociodemographic variable-adjusted multivariate model). The results indicate an association between DRD2 genotype and alcohol consumption habits in humans. These results in the large sample of non-alcoholic males are also opposite to some previous findings on the higher A1 allele frequency among alcoholic populations.

Analysis of monoamine oxidase A (MAOA) promoter polymorphism in Finnish male alcoholics.

Alterations in monoamine oxidase A (MAOA) expression and enzyme activity may be associated with alcoholism and impulsive behavior. Therefore, functional polymorphisms in the MAOA gene would be good candidates to consider in the interindividual differences that exist in the susceptibility to alcoholism. One variant that has been considered as a candidate in alcoholism is a repeat polymorphism in the MAOA gene promoter. We analyzed a cohort of Finnish males with either type 1 or type 2 alcoholism, as well as controls, for differences in the distribution of MAOA promoter alleles. Based on other studies, we postulated that type 2 alcoholism, which is associated with antisocial behavior, but not type 1 alcoholism, would be correlated with the inheritance of the low promoter activity allele. However, we failed to find a difference in allele distribution in type 1 and type 2 alcoholics. In addition, there was no difference in the allele distribution when each group of alcoholics was compared with controls. However, when both groups of alcoholics were pooled and compared with controls, the difference in allele distribution reached a trend towards significance. Our results suggest a minimal association between the MAOA low activity promoter alleles and alcoholism, regardless of the presence or absence of antisocial behavior. Interestingly, approximately 3% of type 2 alcoholics were found to be heterozygous for the MAOA promoter polymorphism. Since MAOA is X-linked, the heterozygotes are probable cases of Klinefelter's syndrome (47,XXY) suggesting that X-chromosome aneuploidy may increase the risk for developing type 2 alcoholism.