Ivo Paclt

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial

BACKGROUND Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinsons, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

The InterSePT scale for suicidal thinking reliability and validity

BACKGROUND The InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies. METHOD In Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined. RESULTS The intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented. CONCLUSION The ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers.

Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactivity disorder: A two-night polysomnographic study with a multiple sleep latency test

OBJECTIVE To evaluate sleep macrostructure, sleep disorders incidence and daytime sleepiness in attention-deficit/hyperactivity disorder (ADHD) affected children compared with controls. METHODS Thirty-one patients (26 boys, 5 girls, mean age 9.3±1.7, age range 6-12 years) with ADHD diagnosed according to DSM-IV criteria, without comorbid psychiatric or other disorders, as never before pharmacologically treated for ADHD. The controls were 26 age- and sex-matched children (22 boys, 4 girls, age range 6-12 years, mean age 9.2±1.5). Nocturnal polysomnography (PSG) was performed for two nights followed by the multiple sleep latency test (MSLT). RESULTS No differences between the two groups comparing both nights were found in the basic sleep macrostructure parameters or in the time (duration) of sleep onset. A first-night effect on sleep variables was apparent in the ADHD group. Occurrence of sleep disorders (sleep-disordered breathing [SDB], periodic limb movements in sleep [PLMS], parasomnias) did not show any significant differences between the investigated groups. A statistically significant difference (p=0.015) was found in the trend of the periodic limb movement index (PLMI) between two nights (a decrease of PLMI in the ADHD group and an increase of PLMI in the control group during the second night). While the mean sleep latency in the MSLT was comparable in both groups, children with ADHD showed significant (sleep latency) inter-test differences (between tests 1 and 2, 1 and 4, 1 and 5, p<0.01). CONCLUSION After the inclusion of adaptation night and exclusion of psychiatric comorbidities, PSG showed no changes in basic sleep parameters or sleep timing, or in the frequency of sleep disorders (SDB, PLMS) in children with ADHD compared with controls, thus not supporting the hypothesis that specific changes in the sleep macrostructure and sleep disturbances are connected with ADHD. A first-night effect on sleep variables was apparent only in the ADHD group. Though we found no proof of increased daytime sleepiness in children with ADHD against the controls, we did find significant vigilance variability during MSLT in the ADHD group, possibly a sign of dysregulated arousal.

Salivary Melatonin Rhythm as a Marker of the Circadian System in Healthy Children and Those With Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Problems with sleep structure, efficiency, and timing have been reported in some, but not all, studies on ADHD children. As the sleep-wake cycle belongs to circadian rhythms, the timekeeping circadian system might be involved in ADHD. To assess whether the circadian system of ADHD children differs from that of controls, the rhythm of the pineal hormone melatonin was used as a reliable marker of the system. Saliva from 34 ADHD and 43 control 6- to 12-yr-old children was sampled at 2-h intervals throughout the entire 24-h cycle, and the melatonin profiles of the ADHD and control children were compared. The nocturnal melatonin peaks of the ADHD and control group did not differ significantly. The high nocturnal interindividual variability of the peaks seen in adulthood was present already in the studied children. The 24-h melatonin profiles of all the ADHD subjects did not differ significantly from those of the control subjects. Categorization of subjects according to age, into groups of 6- to 7-yr-old (9 ADHD, 5 control), 8- to 9-yr-old (16 ADHD, 26 control), and 10- to 12-yr-old (9 ADHD, 12 control) children, revealed significant differences between the ADHD and control group in the melatonin rhythm waveform, but not in nocturnal melatonin peaks; the peaks were about the same in both groups and did not change significantly with increasing age. In the oldest, but not in the younger, children, the melatonin signal duration in the ADHD group was shorter than in the control group. The difference might be due to the fact that whereas in the control group both the evening melatonin onset and the morning offset phase delayed in the oldest children relative to those in the youngest children, in the ADHD group only the onset, but not the offset, phase delayed with increasing age. The data may indicate subtle differences between the circadian system of ADHD and control children during development. (Author correspondence: sumova@biomed.cas.cz)

Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.

Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5‐bisphosphate (PtdIns(4,5)P2), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P2 are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12‐linked PIP5K2A, a member of the phosphatidylinositol 4‐phosphate 5‐kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9‐intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12‐linked psychiatric disorders.

Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: A replication study

Linkage analysis has shown that chromosome 21q22 may contain a candidate gene for bipolar disorder (BPD). One potential 21q22 candidate gene we previously analyzed is SYNJ1, which encodes synaptojanin 1, an inositol 5-phosphatase. Previous mutation screening of SYNJ1 identified three rare functional variants, one of which is a polymorphic variant near the intron 12-oxon 12 border. The rare variants were found only in a total of four BPD patients and no controls, and a trend toward significance was found for the intron 12 polymorphism. In an analysis of a new set of 84 bipolar patients, none of the rare variants were detected. There was an increase in allele 2 for the intron 12 polymorphism, similar to our original study, but the result was not significant. The combined data from both studies continue to show a trend toward significance for allele 2 homozygotes in BPD.

Platelet serotonin uptake in drug-naïve depressive patients before and after treatment with citalopram

We investigated the kinetic parameters of serotonin (5-HT) uptake into platelets in a group of 26 drug-naïve patients suffering from major depression before and after 3-7 weeks of treatment with citalopram. The degree of depression was rated using the Hamilton Depression Rating Scale (HDRS). The 5-HT uptake characteristics in untreated depressive patients were not significantly different from those of normal subjects. The apparent Michaelis constant (K(M)) was significantly increased, the apparent maximal velocity (V(max)) was not different from baseline, and the uptake efficiency (V(max)/K(M)) was significantly decreased after citalopram treatment. A significantly positive correlation between K(M) and V(max) was found in all groups. There was a significantly lower V(max) and V(max)/K(M) in the female compared with the male depressed patients before citalopram treatment; a hypothesis was supported that lowered 5-HT uptake may reflect a gender-linked vulnerability to a serotonin-related depression. A significant negative correlation between 5-HT uptake efficiency and the initial HDRS score suggests that platelet 5-HT uptake can be used as a marker of effective depressive disorder pharmacotherapy. The initial severity of depression was significantly negatively correlated with V(max), which supported a hypothesis that the initial severity of depressive disorder could be related to the lower V(max).

Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.

Objective To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. Methods The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case–control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. Results Homozygosity for a rare putative promoter variant, −1007C→T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the −1007T allele compared with −1007C. Conclusion The data suggest that homozygosity for −1007T could be a rare genetic factor in the development of schizophrenia.

Effect of stimulants on growth of ADHD children: A critical review

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed childhood psychiatric disorders manifested in almost every part of children’s behavior. The most common treatment of ADHD is medication with stimulants, by specific amphetamine and methylphenidate. It is known that the treatment by stimulants may be accompanied by side effects from among decrease of appetite or changes in development as growth suppression and loss of weight which may present very serious phenomenon. Although many studies have monitored changes in growth and weight during medication, they did not provide definite results that the growth and weight suppression are caused by medication or not. According to many studies the height deficit is approximately amounted to 1 cm/year during the first 3 years of the treatment and can be clinically serious. Contrary to these findings some authors reported that the growth or weight changes can be a natural symptom of ADHD and not just a consequence of medication. The present article reviews key studies monitoring changes in parameters of growth in medicated children with ADHD, compares their results and suggest methodology improvements for further studies.