Ilya Reznik

A Highly Significant Association between a COMT Haplotype and Schizophrenia

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

COMT: A common susceptibility gene in bipolar disorder and schizophrenia

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11—a region which includes the catechol‐O‐methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases—and probably also a wider range of behavioral traits.

Combined electroconvulsive-clozapine therapy.

We reviewed 36 reported psychiatric patients who were treated with a combination of electroconvulsive therapy (ECT) and clozapine. The indication of the ECT-clozapine treatment was resistance to classical antipsychotic agents, clozapine, or ECT alone. Sixty-seven percent of the patients benefited from the combined treatment. In most of the patients, the combined treatment was safe and well tolerated. Adverse reactions occurred in 16.6% of the patients and included prolonged ECT-induced seizures (one case), supraventricular (one case) and sinus tachycardia, and blood pressure elevation. It seems that combined ECT-clozapine treatment is effective and safe. This strategy may be a therapeutic option in treatment-resistant patients.

Obsessive and Compulsive Symptoms in Schizophrenia: A Randomized Controlled Trial With Fluvoxamine and Neuroleptics

Obsessive-compulsive-related disorders are frequently comorbid with schizophrenia. The existence of obsessive and compulsive symptoms in patients with schizophrenia represents one of the most severe types of psychotic disorders and may predict a poor prognosis in most cases. Previous pilot studies and case reports have shown that the condition of some patients with schizophrenia did not exacerbate and even improved when serotonin reuptake inhibitors (SSRIs) were added to their standard neuroleptic regimen. The aim of this study was to evaluate the efficacy of a combination treatment of an SSRI (fluvoxamine) and standard neuroleptics for the treatment of obsessive-compulsive (OC) symptomatology in patients with schizophrenia compared with administration of neuroleptics only. Thirty inpatients who met DSM-IV criteria for schizophrenia and also had prominent OC symptoms were randomly divided into two groups. Fourteen patients were treated with conventional neuroleptics and fluvoxamine in doses of 100 to 200 mg/day for 8 weeks. Sixteen patients comprised a control group and received only their previous therapeutic neuroleptic therapy. The patients were assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Scale (CGI) at baseline and endpoint. Side effects were assessed weekly. The data were analyzed using an analysis of variance. A considerable reduction in PANSS (34.3%) and Y-BOCS (29.4%) scores was noted, and CGI scores decreased moderately in both groups. None of the patients showed an acute exacerbation at the end of the study. Side effects were mild and easily tolerated in most patients. This open, randomized, controlled study reveals that coadministration of fluvoxamine, an SSRI, and neuroleptics in patients with schizophrenia and OC symptoms was associated with specific improvements of these symptoms. Thus, the use of an SSRI in treating a patient with schizophrenia and OC symptomatology may be warranted and safe. Other implications of the findings, including general safety of the combined pharmacotherapy and the use of new antipsychotic medications, are also discussed.

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.

Stroop performance in major depression: Selective attention impairment or psychomotor slowness?

BACKGROUND Numerous neuropsychological studies reported impaired Stroop performance in major depressive disorder (MDD) patients. METHODS The present study attempted to identify possible neuropsychological mechanisms involved in this impairment in untreated MDD outpatients (n=75) as compared to healthy subjects (n=83). Inspection Time, Finger Tapping, Simple and Choice Reaction Time were considered as measures of perceptual, motor, psychomotor speed, and response selection, respectively. RESULTS MDD patients performed significantly slower than healthy controls in the neutral and the congruent conditions, but not in the incongruent ones. In order to identify predictors of Stroop performance, linear hierarchical regressions analyses were performed. Age, motor and psychomotor speed were predictors of response time and accuracy on Stroop performance. Significant correlations between response time and the number of errors in all three Stroop conditions were found in MDD patients, while such a correlation was obtained in the healthy controls only in the incongruent condition. LIMITATIONS Although education was included as a covariate in our analyses, suggesting that the observed effects could not be ascribed to education differences, further testing with education-matched samples is warranted. CONCLUSIONS Our study shows that the Stroop task performance is affected by both aging and MDD. Impairment in the Stroop performance can be predicted by psychomotor slowness and by vigilance level in MDD outpatients, but not by impairment of selective attention per se.

An open study of fluvoxamine augmentation of neuroleptics in schizophrenia with obsessive and compulsive symptoms.

Patients whose schizophrenia is characterized by marked obsessive-compulsive features can be difficult to treat successfully and often require a combination treatment. The aim of this open-label study was to evaluate the efficacy and tolerability of an addition of fluvoxamine—a selective serotonin reuptake inhibitor (SSRI)—to standard neuroleptics in treatment of obsessive-compulsive (OC) symptomatology in patients with schizophrenia. Sixteen patients with schizophrenia were treated with conventional neuroleptics and fluvoxamine in doses of 100–200 mg/d for 8 weeks. The patients were assessed with use of the Brief Psychiatric Rating Scale (BPRS) and the Yale Brown Obsessive-Compulsive Scale (YBOCS) at baseline and endpoint. Results included considerable reduction in BPRS (39.4%) and Y-BOCS (32.9%) scores. None of the patients showed an acute exacerbation during the whole study period. Side effects were clinically insignificant. This open-label trial supports previous suggestions that coadministration of SSRIs and neuroleptics in patients with schizophrenia with OC symptoms is associated with robust improvements of these symptoms. Therefore, the use of SSRIs in patients with schizophrenia with OC symptomatology may be warranted and safe.

The significance of the nitric oxide in electro-convulsive therapy: a proposed neurophysiological mechanism.

Electroconvulsive therapy (ECT) is used to treat patients with major depressive disorder, manic episodes and other serious mental disorders. Virtually every neurotransmitter system is affected in ECT. The significance of the nitric oxide (NO), which has an established role as a neurotransmitter, neuromodulator, and an intraneuronal second messenger, in ECT is still not clear. We described the involvement of NO in long-term potentiation, the N-methyl-D-aspartic acid (NMDA) receptor activity, regulation of cerebral blood flow, and the hypothalamic-pituitary axis and propose that this involvement is critical in ECTs efficiency, treatment refractoriness, and neuropsychological sequelae by its influences on these systems. Nitric oxides significant role in other pathophysiological mechanisms has led to current therapeutic protocols and may be applicable in this setting.

Myotoxicity and neurotoxicity during clozapine treatment

Some recent studies have shown that clozapine (CLZ) has myopathic side effects and causes alterations in motor force control. The aim of this study was to evaluate the neurologic and electrophysiologic characteristics of patients with schizophrenia who are undergoing long-term CLZ treatment. Ninety-four patients with schizophrenia treated with CLZ for 18.2 ± 15.5 months were studied retrospectively and prospectively (40% and 60%, respectively) for serum creatine kinase (CK) levels before and after initiation of CLZ treatment. An electrodiagnostic study was performed on patients with CK elevation above normal limits, complained of general weakness or muscle pains, and/or had abnormal clinically significant findings. In 13 patients (13.8%), abnormal CK levels were found. Six patients complained of some muscular weakness. In two patients, clinical assessment revealed mild general muscular weakness; one revealed decreased tendon reflexes and, in both, CK levels were above 1,750 IU/L. On electrophysiologic examinations performed in the six patients with abnormal neurologic findings, the motor and sensory nerve conduction velocity were within normal range in all but one patient, who exhibited some prolongation of distal latency in the lower limbs. In two patients, the electromyography demonstrated a myopathic pattern. In 2.1% of medically healthy patients with schizophrenia treated with clozapine on a long-term basis, signs of myotoxicity were found. It seems warranted to discontinue CLZ therapy in patients who exhibit abnormal CK levels and myopathic features during treatment. Further studies are needed to provide more objective data on the impact of CLZ treatment on muscle tissue.

β-Adrenergic Antagonists for the Treatment of Clozapine-Induced Sinus Tachycardia: A Retrospective Study

C lozapine is an atypical antipsychotic agent with well-documented superiority over other antipsychotics in the treatment of patients with treatment-resistant schizophrenia, reducing negative, affective symptoms and improving cognitive deficits. Because clozapine has no substitute in clinical psychiatry, its adverse effect management continues to pose an extraordinary medical challenge. One of the most important and least investigated clozapine adverse effects is sympathetic hyperactivity and decreased heart rate (HR) variability, which may account for the increased frequency of arrhythmias, myocarditis, cardiomyopathy, and sudden death observed in patients with clozapine treatment. For example, the rate of myocarditis in clozapine-treated patients seems to be 17 to 322 times greater than that of the general population, and it is associated with an increased risk of fatal myocarditis, that is, 14 to 161 times greater than that of the general population. The clinical features of myocarditis are varied. The spectrum includes asymptomatic patients who may show abnormalities in the electrocardiogram (ECG), patients with signs and symptoms of clinical heart failure and ventricular dilatation, and patients with symptoms of fulminant heart failure and severe left ventricular dysfunction, with or without cardiac dilatation. Patients may present with a history of a recent flulike syndrome accompanied by fever, arthralgias, and malaise. Laboratory tests may show leukocytosis, an elevated sedimentation rate, eosinophilia, or an elevation in the cardiac fraction of creatine kinase. The ECG may show ventricular arrhythmias or heart block, or it may mimic the findings in acute myocardial infarction or pericarditis. Tachycardia has been noted as a presenting sign of myocarditis and, along with low values of HR variability, may predict malignant arrhythmias such as sustained ventricular tachycardia and sudden death. Clozapine-induced sympathetic hyperactivity that usually presents with tachycardia is a significant clinical problem with no established pharmacological prevention and treatment. In many cases, clozapine-induced tachycardia results in discontinuation of clozapine, leaving those patients with treatment-resistant schizophrenia without the most effective pharmacological treatment of this devastating mental condition. A-Adrenergic antagonist agents (BAAA) are widely used for the prevention and treatment of the cardiovascular consequences of sympathetic hyperactivity. By blocking peripheral A receptors, A-adrenergic antagonists improve sympathetic balance by decreasing sympathetic nervous system activity and increasing parasympathetic activity, as well as increasing HR variability, conferring cardiac protection through the prevention of tachyarrhythmias, cardiomyopathies, and sudden death. We suggest that administration of A-adrenergic antagonists may reverse sinus tachycardia caused by clozapine treatment. To test this suggestion, we assessed retrospectively, by chart review, the efficacy of A-adrenergic antagonist administration on clozapine-induced sinus tachycardia in patients with schizophrenia.