Israeli preschoolers under Scud missile attacks. A developmental perspective on risk-modifying factors.

BACKGROUND: The devastating effects of traumatic events on children are modulated by risk and protective factors. This study examines the differential effects of traumatic displacement of preschool children and their families following Scud missile attacks on Israel during the Persian Gulf War. METHODS: Three groups participated in the study: families displaced after their houses were damaged, undisplaced families from the same neighborhood (without home damage), and families from a distant city that was threatened but not directly attacked. Data concerning the traumatic event, the child (personality, internalizing, externalizing, and stress symptoms), the mother (Symptom Checklist-90-Revised), and the family (Family Adaptability and Cohesion Evaluation Scales) were gathered 6 months after the end of the war. RESULTS: Displaced children and mothers showed higher externalizing and stress symptom levels compared with undisplaced and threatened subjects. Destruction of the house and displacement, but not mere distance from the missile impact, explained symptomatic behavior. Inadequate family cohesion predicted symptomatic reaction for 3- and 4-year-old children but not for older ones. CONCLUSION: Both human and nonhuman factors contribute to the preschool child's adaptive mechanisms that regulate environmental stressful stimuli. These risk-modifying factors become more autonomous of caretakers with increasing age.

Platelet imipramine binding and plasma cortisol levels in Israeli civilians during the Gulf War.

[3H] Imipramine binding to platelets and plasma cortisol levels were measured in nine Israeli civilians before, during, and after repeated missile attacks. Hamilton Anxiety Rating Scale (HARS), and Beck Depression Inventory (BDI) were similar before and during the war and decreased significantly after the war. A trend toward increase in platelet imipramine binding values was observed during the war when compared with the postwar values (19%; p = 0.056), and/or when compared with prewar values (26%; p = 0.063). However, one-way analysis of variance with repeated measures did not reveal a significant statistical difference [F (2,6) = p = 2.07; NS] among the three time points. A significant correlation was found between HARS score, but not BDI, and imipramine binding values in the prewar and postwar time points (r = 0.87; 0.71, respectively). Plasma cortisol levels did not alter significantly during the study period.

Cytokine production in obsessive-compulsive disorder.

Cytokine production was previously demonstrated to be reduced in untreated major affective patients. In addition, recovery from depression following clomipramine (CMI) treatment was accompanied by the restoration of interleukin-1 beta (IL-1 beta) and interleukin-3-like activity (IL-3-LA) to normal range. In the present study we assessed the in vitro production of IL-1 beta IL-2, and IL-3-LA by peripheral blood mononuclear cells (PBMC) in 11 nondepressed patients with obsessive compulsive disorder (OCD) before and after 8 weeks of CMI treatment. Results were compared with those of 11 healthy subjects. CMI treatment induced a significant improvement in OCD symptoms. No alteration was observed in cytokine production in OCD patients before treatment as compared to control subjects. Moreover, 8 weeks of drug treatment had no effect on cytokine production. In conclusion, OCD per se, as well as CMI treatment, have no effect on interleukin production as measured in this study.

T-cell subsets in acute psychotic schizophrenic patients.

Two-color flow cytometric analysis was performed on peripheral blood lymphocytes of 16 untreated schizophrenic patients during an acute psychotic attack and 16 healthy control subjects to evaluate differences in T-cell subpopulations. In schizophrenic patients, we observed decrease in CD4+ 2H4+ (suppressor-inducer) and CD8+ 2H4+ (suppressor-effector) T-cell subsets. The selective loss of 2H4+ cell markers both on helper and suppressor T cells was not correlated to the severity of the acute psychosis. Our results may indicate a mechanism of an immune disequilibrium in schizophrenic patients during an acute psychotic attack.

Cytokine production in major depressed patients before and after clomipramine treatment.

Cytokine production by peripheral blood mononuclear cells (PBMC) was assessed in 10 major depressed patients (5 men and 5 women) before and after 4 weeks of clomipramine treatment and in age- and gender-matched healthy controls. A significant reduction in interleukin-1B (IL-1B), interleukin-2 (IL-2) and interleukin-3-like activity (IL-3-LA) was observed in untreated depressed patients when compared to controls. IL-1B and IL-3-LA synthesis was significantly increased after drug treatment. The suppression of cytokine production by PBMC in depressed patients may be attributed to the depression per se, or it may be related to depression-associated hyperactivity of the hypothalamic-pituitary-adrenal axis. The mode of interaction between depression and cellular immune function and the mediators responsible for the reduced cytokine production need to be studied further.

Interaction between antidepressants and phosphoinositide signal transduction system in human platelets.

The present study was designed to evaluate the inhibitory effect of antidepressants on thrombin-induced phosphoinositide (PI) hydrolysis. Thrombin 5 units/ml induced a 100%-200% increase in platelet inositol phosphates (IPs) formation. This effect was inhibited in a dose-dependent manner by various heterocyclic antidepressants (IC50 40-170 mumol/L) The monoamine oxidase inhibitor, phenelzine, in concentrations up to 500 mumol/L, was devoid of inhibitory activity. The tricyclic antidepressants, (50 mumol/L) inhibited also thrombin-induced platelet aggregation by 32%-47%. No alteration in thrombin-induced IPs formation was detected in recovered major depressed patients (n = 15) maintained on clomipramine (75-150 mg/day). These results indicate that the heterocyclic antidepressants interfere with the thrombin-linked PI-signaling system. However, the inhibitory effect is achieved only in concentrations above the plasma concentrations obtained with therapeutic doses of these agents.

Serum triiodothyronine elevation with posttraumatic stress disorder: a cross-cultural study.

This study examines the thyroid hormonal profile in Israeli combat veterans with posttraumatic stress disorder (PTSD) and compares it with the previously reported profile in American Vietnam combat veterans with PTSD. Eleven male combat veterans with PTSD were compared with 11 normal subjects. Thyroid junction was evaluated by the measurement of serum total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), free thyroxine (FT4), thyroxine-binding globulin (TBG), and thyroid-stimulating hormone (TSH). The mean total T3 level in the Israeli PTSD patients (160.5 ng/dL) was significantly elevated (t = 2.53, p < .02) above that of the comparison group (135.5 ng/dL). Total T3 mean levels were not significantly different between the Israeli PTSD group and two American PTSD groups, but all three PTSD groups had significantly higher total T3 levels than both Israeli and American comparison groups. This preliminary study indicates that T3 elevation in combat-related PTSD may extend across cultures and suggests that further comparison of Israeli and American PTSD and normal groups may be useful in evaluating the significance and implications of the unusual alterations in the thyroid system in PTSD.

Mothers' functioning and children's symptoms 5 years after a SCUD missile attack.

OBJECTIVE: The authors assessed the long-term consequences of the SCUD missile attack in Israel on children as a function of their mothers' psychological functioning, family cohesion, and the event itself. METHOD: Five years after the Gulf War, the authors assessed the internalizing, externalizing, stress, and posttraumatic symptoms of 81 children aged 8-10 years whose homes were damaged in the SCUD missile attack, as well as general and posttraumatic symptoms, defensive style, and object relations in their mothers. RESULTS: There was a significant decrease in severity in most symptom domains and an increase in avoidant symptoms in the children. Greater severity of symptoms was associated with being displaced, living in a family with inadequate cohesion, and having a mother with poor psychological functioning. The association between the symptoms of children and mothers was stronger among the younger children. Posttraumatic symptoms increased in one-third of the children and decreased in one-third over the last 30 months of the study. Severe posttraumatic symptoms were reported in 8% of the children. CONCLUSIONS: Despite a continuous decrease in symptom severity, risk factors identified shortly after the Gulf War continued to exert their influence on children 5 years after the traumatic exposure.

Impact of the Gulf War on the anxiety, cortisol, and growth hormone levels of Israeli civilians.

OBJECTIVE: The authors investigated the impact of continuous and repeated stress on Israeli civilians exposed to missile attacks during the Gulf War. METHOD: Study 1 included 26 healthy volunteers aged 28-59 years. Their scores on the Hamilton Anxiety Rating Scale and levels of plasma cortisol and growth hormone (GH) were evaluated before, during, and after the war. Study 2 included 13 healthy volunteers aged 25-59 years. Their scores on the state portion of the State-Trait Anxiety Inventory and levels of cortisol and GH were measured three times daily (8:00 a.m., noon, and 6:00 p.m.) at two time points (during and after the war). RESULTS: Anxiety levels of civilians exposed to the threat of war and later to actual missile attacks were significantly higher before and during the war than afterward. Anxiety during the war reached a peak in the evening. The increase in anxiety was not accompanied by any change from basal morning cortisol and GH levels or by diurnal variations in these hormones. CONCLUSIONS: Anxiety levels during the war were similar to those 1 day before its onset, which can be explained by the nature of coping processes. During the war, anxiety levels were highest in the evening, reflecting the war routine (missile attacks occurred mostly at night). The unaltered hormone levels and their normal diurnal variations despite the subjects' persistent anxiety were probably due to adaptation of the hypothalamic-pituitary-adrenal and hypothalamic-somatotropin axes to continuous stress.

Alteration of platelet benzodiazepine receptors by stress of war.

Mitochondrial benzodiazepine receptors play a major role in steroidogenesis. The authors determined plasma cortisol levels, platelet levels of mitochondrial benzodiazepine receptors, and anxiety and depression scores in 11 civilians exposed to the Persian Gulf war. The density of mitochondrial benzodiazepine receptors was 22% and 15% lower before and during the war, respectively, than 4 weeks after the end of the war. Relief of stress led to an increase in receptors, which correlated with the improvement in anxiety but not mood.

Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder.

Peripheral-type benzodiazephine receptors (PBR) are involved in steroidogenesis and are sensitive to stress. Reduced platelet PBR density has been demonstrated in generalized anxiety disorder (GAD), but not in obsessive-compulsive disorder (OCD). We extended this observation to another anxiety disorder, namely, posttraumatic stress disorder (PTSD). Eighteen post-Persian Gulf War PTSD patients and 17 age- and sex-matched controls were included in the study. All subjects were evaluated using the Structured Clinical Interview for DSM-III-R-Patient Version. The severity of symptoms was assessed using the DSM-III-R scale for PTSD, the Impact of Event Scale, the Beck Depression Inventory, and the State-Trait Anxiety Inventory. [3H]PK 11195 was used to label platelet PBR. All psychological parameters (except trait anxiety) were higher in PTSD patients compared to controls. Decreased platelet PBR density (-62%; p < .001) was observed in the PTSD patients compared to controls. The reduction in PBR observed in PTSD patients was in accordance with the findings in GAD patients, but differed from those obtained in OCD patients. It is possible that the receptoral downregulation is an adaptive response aimed at preventing chronic overproduction of glucocorticoids in hyperarousal states.

Sympathetic pupillary activity in infants.

In an attempt to learn the contribution of the sympathetic system to smaller pupillary size in infants, pupillary responses were tested to agents acting on this system in 12 ihfants and 23 young adults. Phenylephrine dilated the pupils of both groups by the same ratio, with infants' pupils reaching a lesser diameter. The responses to cocaine and hydroxyamphetamine were lower in children. It is concluded that in the first months of life the postganglionic sympathetic nerve releases less norepinephrine. This may be due to a lower number of sympathetic neurons. The post-synaptic apparatus may not be fully developed in infants.

A second conponent of atropine mydriasis.

A patient with Waardenburg syndrome had, in addition to the classical findings, a semidilated fixed pupil which did not react to changes of illumination, to convergence, or to pilocarpine of phospholine iodide. However, it responded normally to locally applied drugs acting on the sympathetic system. The pupil dilated after application of atropine, homatropine, or cocaine. The effect of cocaine, but not of atropine and homatropine, was prevented by pretreatment with guanethidine. It is concluded that the mydriasis caused by atropine and homatropine is partly dependent upon a direct action on the radial smooth muscle.

Use of atypical neuroleptics in child and adolescent psychiatry.

BACKGROUND: This article reviews the published clinical experience with atypical neuroleptics in children and adolescents. METHOD: A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug. RESULTS: We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder. CONCLUSION: The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Sympathetic pupillary tone in old age.

In an attempt to determine whether autonomic neural factors might be involved in senile miosis, we tested pupillary responses to agents acting on the ocular sympathetic system in old subjects and compared them to responses in young adults. Our results suggest that sympathetic tone is decreased in the elderly. The dilator pupillae muscle does not lose its sensitivity to norepinephrine with age.

Platelet adenylate cyclase activity in Israeli victims of Iraqi Scud missile attacks with post-traumatic stress disorder.

Platelet adenylate cyclase activity was measured in 16 control subjects and 16 patients who developed post-traumatic stress disorder (PTSD) as a result of damage inflicted on their homes during the Iraqi Scud missile attacks on Israel which occurred during the 1991 Gulf War. There were no differences in basal, NaF-stimulated, PGE1-stimulated or forskolin-stimulated activity between controls and PTSD subjects. Epinephrine inhibition of forskolin-stimulated activity, an effect mediated by alpha 2 adrenergic receptors, was slightly but not significantly increased in the PTSD patients compared to the controls, while 5-HT induced inhibition, an effect mediated by putative 5-HT1a-like receptors, was unchanged. The relationship of these activities to measures of anxiety and depression in these patients is discussed.

Visual search in schizophrenia: latent inhibition and novel pop-out effects.

A visual search task was used to assess attentional function in a mixed group of schizophrenic patients and in normal controls. Subjects identified presence or absence of a unique shape presented with homogeneous distractors. Response time (RT) was examined as a function of prior experience with target, distractor, or both. On each trial, targets and/or distractors were either novel or familiar. Schizophrenic patients were slower than controls in all conditions. In the test phase, three target/distractor conditions were examined (PE - target and distractors pre-exposed but reversed; NPE - target novel and distractors pre-exposed; NOV - novel target and distractors). As predicted, normal controls, but not schizophrenics, showed latent inhibition (LI: PE minus NPE). The latter finding was due to the absence of normal LI in female patients. A novel pop-out effect (NOV minus NPE) was obtained which did not interact with any of the other variables. The results suggest that the LI effect is indeed related to the processing of irrelevant stimuli, and that, at least female schizophrenic patients process such stimuli differently from controls. Past inconsistencies in the LI-schizophrenia literature may be the result of disproportionate gender compositions in patient and control groups.

A rare short allele of the serotonin transporter promoter region (5-HTTLPR) found in an aggressive schizophrenic patient of Jewish Libyan origin.

The serotonin transporter gene (SLC6A4), which plays a key role in the serotonergic pathway in the brain, is a candidate for mediating genetic susceptibility to various psychiatric disorders. There are two predominant alleles in the polymorphic promotor region [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] of this gene: a long and a short allele with 16 and 14 repeat units, respectively. The short allele has lower activity and is associated with several psychiatric disorders and personality traits. We identified and sequenced a novel allele with 13 repeat units, 23 base pairs shorter than the common short allele. This unique allele was detected in a schizophrenic patient of Jewish Libyan origin. The patient exhibited extreme aggressive behavior and committed suicide after several attempts. The novel short allele was not detected in 172 healthy control subjects and 361 patients with various mental disorders. The presence of a very short unique allele in a severely aggressive schizophrenic patient may reflect a specific effect on the particular phenotype, although it is unlikely that this allele has a major contribution to susceptibility to schizophrenia. The role of the allele in serotonin transport and possible association with disease phenotype should be further investigated.

The prevalence of mitral valve prolapse in children with anxiety disorders.

Studies in adults have suggested a comorbidity of mitral valve prolapse and anxiety disorders, especially panic disorder. The nature of the association between these disorders is yet unclear. In the last years, case studies have appeared, reporting on the comorbidity of anxiety disorders and mitral valve prolapse in children. The present study evaluated the prevalence of mitral valve prolapse in children with anxiety disorders as compared to normal controls. The study group consisted of 52 children, 6-18 years old, with a diagnosis of panic disorder (9.6%), separation anxiety disorder (65.4%) and/or overanxious disorder (61.5%). Fifty-one normal age- and gender-matched healthy children served as controls. All participants were evaluated for the presence of mitral valve prolapse by cardiac auscultation and echocardiography. None of the 52 children with anxiety disorder and one of the 51 control children (1.96%) had mitral valve prolapse. There appears to be no association between childhood anxiety disorders and mitral valve prolapse. Whether children with panic disorder proper show a greater prevalence of mitral valve prolapse remains an open question. Implications to the association of mitral valve prolapse and panic disorder are discussed.

Thyroid function in attention deficit and hyperactivity disorder.

In view of the recent conflicting findings regarding the causative role of thyroid abnormalities in attention deficit hyperactivity disorder (ADHD), we performed a replication study to clarify the issue and establish clinical guidelines. Thyroid tests were performed in 43 ADHD children and 28 age- and gender-matched controls. Sixteen ADHD children showed total triiodothyronine (TT3) levels which were slightly above the upper limit of normal, but no significant difference in TT3 values was noted between the ADHD and the control groups. Moreover, none of the ADHD subjects had abnormal levels of total thyroxine, free thyroxine, thyroid stimulating hormone or total triiodothyronine reuptake. The present study supplies additional evidence for the lack of an association between thyroid function and ADHD, and counters the suggestion that thyroid function be routinely screened for in ADHD children.