The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia.

Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone (PREG), and their sulfates (DHEAS and PREGS) display multiple effects on the central nervous system. Specifically, neurosteroids have various functions associated with neuroprotection, response to stress, mood regulation, and cognitive performance. In addition, neurosteroid levels are altered in stress-related neuropsychiatric disorders. This review focuses on the alterations of these neurosteroids in schizophrenia and on their association with clinical and neurocognitive manifestations. As described henceforth, findings from clinical studies have revealed that PREG, DHEA, and their sulfates might be involved in the pathophysiology of schizophrenia, and in some of its manifestations. Clinical trials for the evaluation of these neurosteroids face challenges in terms of experimental design, dosing strategy, data analysis, and interpretation. The review concludes with a list of suggested topics for future research. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Is the WKL1 gene associated with schizophrenia?

A missense mutation Leu309Met in the WKL1 (MLC1, KIAA0027) gene, mapped to 22q13.3, was reported to co-segregate with periodic catatonic schizophrenia (SCZ) in a single large German pedigree with seven affected individuals (Meyer et al. [2001: Mol Psychiatry 6:302-306]). This report raised the following questions that were dealt with in the present study: does the Leu309Met mutation have a role in SCZ, or only in catatonic SCZ? Does the mutation Leu309Met in the WKL1 gene, encoding a putative membrane protein, non-selective cation channel, have any effect on the channel activity? Is the WKL1 gene, which is expressed exclusively in brain, expressed differently in SCZ brains compared to controls? These questions were answered by screening the Leu309Met mutation in 117 Israeli Jewish patients with SCZ (55 Ashkenazi and 62 non-Ashkenazi Jews) and 176 matched controls. In search of differences in the level of WKL1 gene expression, postmortem dorsalateral prefrontal cortex of 16 schizophrenic patients and 15 controls was checked. We also measured the putative channel activity of normal WKL1 subcloned in pcDNA3 to determine the effect of the reported Leu309Met mutation. Our results argue against the involvement of WKL1 in SCZ susceptibility.

Quality of life and coping with schizophrenia symptoms.

The question addressed in this paper is whether different coping styles mediate the relationship between psychopathology and related distress and the quality of life (QOL) among patients with schizophrenia. In a cross-sectional design, 161 schizophrenia inpatients were comprehensively evaluated with standardized measures of QOL, psychopathology, psychological distress and coping styles. Correlations and regression analyses were performed to examine the relationship among parameters and to estimate the mediating effect of coping styles on QOL in the framework of a distress/protection model. Life quality correlated positively with task- and avoidance-oriented coping styles and slightly negatively with emotion-oriented coping. Emotion-oriented coping mediated the relationship between the severity of activation, anxiety/depression symptoms, and QOL, while avoidance-oriented (distraction) coping was mediated between QOL and paranoid symptoms. Coping styles accounted for 25% of the variance in subjective QOL scores compared with 15% for psychological distress, and only 3% for clinical variables. The ability to cope with symptoms and associated distress substantially contributes to QOL appraisal in schizophrenia. Thus, different coping strategies may reduce the negative influence of specific symptoms and related distress on the subjective QOL of schizophrenia patients.

Clinical evaluation of prior suicide attempts and suicide risk in psychiatric inpatients.

BACKGROUND: In practice psychiatrists rely on their own experience and intuition to evaluate the suicide potential of individual patients, but the algorithms for the decision-making process remain unclear. OBJECTIVES: (1) to establish models for the decision making process for evaluating suicide risk; (2) to simulate the impact of information concerning the number of previous suicide attempts on the clinician's ability to detect patients who performed medically serious suicide attempts (MSSAs). METHODS: Four decision models (linear, dichotomized, hyperbolic, and undifferentiated) depicting the influence of the number of previous suicide attempts on the clinician's recognition of MSSAs in 250 psychiatric inpatients were elicited and tested by a series of discriminant analyses. RESULTS: The dichotomized model ("all or none") was found to be the most efficient in detecting medically serious suicide attempts. CONCLUSION: The "all or none" paradigm seems to be the most appropriate way to evaluate the weight of previous suicide attempts in the decision-making process identifying medically serious suicide attempt patients.

Subjective quality of life in severely mentally ill patients: a comparison of two instruments.

Although many quality of life (QOL) scales have been developed, comparison of specific QOL instruments is lacking. We compared the psychometric properties of two QOL measures in parallel samples of mentally disturbed and non-patient subjects. We simultaneously administered the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and self-report items of the Lancashire Quality of Life Profile (LQOLP) to 199 patients with severe mental disorders and 175 non-patients. The patients were evaluated with psychiatric rating scales. We identified five concordant domains, and five instrument-specific domains for the LQOLP and four for the Q-LES-Q. The Q-LES-Q provides better psychometric properties than the LQOLP in both samples. Both instruments show a good capacity to evaluate QOL and discriminate between the patients and non-patient controls. Within the patient sample, both QOL measures showed similarly negative correlations with severity of depression, but not mania, positive, negative, and general symptomatology. Both instruments proved to be mental health related, but neither was mental-disorder specific. Despite the acceptable psychometric properties and correlation of general QOL indices, similar QOL domains proved to be instrument specific and not sufficiently compatible. These discrepancies should be considered when comparing evaluations from similar domains in these QOL scales.

Validation of the Computerized Suicide Risk Scale--a backpropagation neural network instrument (CSRS-BP).

BACKGROUND: Medically serious suicide attempts have been recognized as the most important predictor of suicide. The Computerized Suicide Risk Scale based on backpropagation neural networks (CSRS-BP) has been recently found efficient in the detection of records of patients who performed medically serious suicide attempts (MSSA). OBJECTIVES. To validate the CSRS-BP by: 1) using the CSRS-BP with patients instead of records; 2) comparing the ability of expert psychiatrists to detect MSSA, using the CSRS checklist; and 3) comparing the results of the Risk Estimator for Suicide (RES) and the self-rating Suicide Risk Scale (SRS) with the CSRS-BP. METHODS: Two hundred fifty psychiatric inpatients (35 MSSA and 215 non-MSSA) were diagnosed by clinicians using the SCID DSM-IV. Three expert psychiatrists completed the CSRS checklist, and the RES for each patient, and the patients completed the self-report SRS assessment scale. The CSRS-BP was run for each patient. Five other expert psychiatrists assessed the CSRS checklists and estimated the probability of MSSA for each patient. Comparisons of sensitivity and specificity rates between CSRS-BP, assessment scales and experts were done. RESULTS: Initially, the CSRS-BP, RES, SRS, and experts performed poorly. Although sensitivity and specificity rates significantly improved (two to four times) after the inclusion of information regarding the number of previous suicide attempts in the input data set, results still remained insignificant. CONCLUSIONS: The CSRS-BP, which was very successful in the detection of MSSA patient records, failed to detect MSSA patients in face-to-face interviews. Information regarding previous suicide attempts is an important MSSA predictor, but remains insufficient for the detection of MSSA in individual patients. The detection rate of the SRS and RES scales was also poor and could therefore not identify MSSA patients or be used to validate the CSRS-BP.

Phospholipid patterns of erythrocytes in schizophrenia: relationships to symptomatology.

The phospholipid composition of red blood cells (RBC) from 32 haloperidol-treated schizophrenic patients, classified according to the positive and negative syndrome scale (PANSS) as showing either predominantly positive or predominantly negative symptoms, was determined and compared with that of normal controls. While the levels of phosphatidylcholine and phosphatidylserine were similar in all three groups, sphingomyelin (SM) and phosphatidylethanolamine (PE) were, respectively, increased and decreased in RBCs of schizophrenic patients. In both patient groups, the SM/PE ratios correlated directly with the PANSS negative symptom scale scores and inversely with the positive symptom scale scores. However, the inverse changes in the contents of SM and PE were much more expressed in the negative group. It is suggested that a main source of that difference is a higher activity of the polyunsaturated acid-selective phospholipase A(2) in the negative syndrome patients than in the positive syndrome and control groups.

Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study.

Treatment of aggression in schizophrenic patients is a major challenge. We sought to examine the efficacy of augmentation of antipsychotic treatment with pindolol in the amelioration of aggression. Thirty male inpatients meeting DSM-IV criteria for schizophrenia, aged 20-65 years involved in four or more aggressive incidents in the two previous months, were enrolled in a double-blind crossover study. Aggression was evaluated per incident, with the Overt Aggression Scale (OAS). Positive and Negative Syndrome Scale (PANSS) was administered at baseline, crossover and at endpoint. Patients received either pindolol or placebo augmentation 5 mg x three times a day until crossover, then switched. No significant differences were found in the PANSS scores between the placebo and pindolol treatments. OAS scores were significantly reduced for number of aggressive incidents towards objects and other persons during pindolol treatment (0.59 versus 1.46, F = 6.09, P < 0.02; 1.96 versus 3.23, F = 4.17, P < 0.05, respectively). Similar results were obtained for severity of incidents (0.89 versus 3.58, F = 19.42, P < 0.0001; 2.89 versus 6.85, F = 10.11, P < 0.004, respectively). Pindolol, with its dual beta and 5-HT1A blocking effect ameliorated both number and severity of aggressive acts. Influence on severity may be associated with a 5-HT1A antagonistic effect.

Gender differences in psychosocial risk factors for psychological distress among immigrants.

The reasons for a greater prevalence of psychological distress among women than men remain unknown. We sought to test two hypotheses that gender operates either as (1) a moderator or (2) a mediator between psychosocial risk factors and experienced distress. A cross-sectional community survey of 1,062 adult Russian-born Jewish immigrants to Israel was conducted. The Demographic Psychosocial Inventory (DPSI) and the Talbieh Brief Distress Inventory (TBDI) were used to measure the parameters of interest. Univariate and multivariate analyses were used to test the moderation versus mediational hypotheses of gender in the stress-distress relationship. The aggregate levels of psychological distress and depression, anxiety, and obsessive symptoms were significantly higher for women than for men. Five sources of distress were more likely to be reported by women: family problems, inappropriate climatic conditions, anxiety about the future, poor health status, and uncertainty in the present life situation. Men scored higher on three stress-protective factors: the number of reasons for immigration, commitment to the host country, and job adequacy. Results of multiple regression and multivariate analysis of variance (MANOVA) supported the mediation hypothesis that gender differences in psychological distress stem from women's greater exposure to specific psychosocial stressors. Our findings demonstrate the validity of gender as an important mediating mechanism underlying the differential perception of risk factors for the development of psychological distress.

Increased prevalence of negative life events in subtypes of major depressive disorder.

The prevalence of negative life events is known to be increased among patients with depression. Little data exist on the specific subtypes of depression that are related to negative life events. Our study aimed to address this issue. We compare 115 patients with major depressive disorder (MDD) to 60 normal controls. MDD patients reported experiencing one (P = .0001) or two (P = .01) negative life events more frequently than controls. Patients reported marital, other personal problems, and medical events significantly more often than controls (P < .01). Patients did not report more positive life events, and did not attribute greater severity to their adversities than controls. Younger MDD patients experienced four (P = .01) negative life events significantly more often than older patients. Similarly, patients with mild-moderate depression, nonmelancholic depression, or first episode of depression (FDE), respectively, experienced three or four life events significantly more often than patients with severe, melancholic, or recurrent depression (RDE). Other patient and illness characteristics such as gender, early parental loss, family history of depression or other mental disorders, psychotic features, suicide attempts, and chronicity were not related to increased prevalence of negative life events. Our results support the hypothesis that a subset of patients with MDD is especially prone to suffer from a cluster of negative life events. This subgroup is at increased risk for relapse and poor prognosis. The implications of these results for further research and for treatment are discussed.

Differences in quality of life domains and psychopathologic and psychosocial factors in psychiatric patients.

BACKGROUND: Although treatment of severe mental disorders should strive to optimize quality of life (QOL) for the individual patient, little is known about variations in QOL domains and related psychopathologic and psychosocial factors in patients suffering from schizophrenia, schizoaffective disorder, and/or mood disorders. We hypothesized that QOL in severe mental disorder patients would have a more substantial relationship with psychosocial factors than with illness-associated factors. METHOD: A case-control, cross-sectional design was used to examine QOL of 210 inpatients who met DSM-IV criteria for a severe mental disorder and who were consecutively admitted to closed, open, and rehabilitation wards. Following psychiatric examination, 210 inpatients were assessed using standardized self-report measures of QOL, insight, medication side effects, psychological distress, self-esteem, self-efficacy, coping, expressed emotion, and social support. QOL ratings for patients and a matched control group (175 nonpatients) were compared. Regression and factor analyses were used to compare multidimensional variables between patients with schizophrenia and schizoaffective and mood disorders. RESULTS: In all QOL domains, patients were less satisfied than nonpatient controls. Patients with schizophrenia reported less satisfaction with social relationships and medication when compared with patients with schizoaffective and/or mood disorders. Regression analysis established differential clusters of predictors for each group of patients and for various domains of QOL. On the basis of the results of factor analysis, we propose a distress protection model to enhance life satisfaction for severe mental disorder patients. CONCLUSION: Psychosocial factors rather than psychopathologic symptoms affect subjective QOL of hospitalized patients with severe mental disorders. The findings enable better understanding of the combining effects of psychopathology and psychosocial factors on subjective life satisfaction and highlight targets for more effective intervention and rehabilitation.

Touch feel illusion in schizophrenic patients.

BACKGROUND: The rubber hand illusion is a tactile sensation referred to as an alien limb. The illusion has been explained by a spurious reconciliation of visual and tactile inputs reflecting functional connectivity in the brain and was used to explore alterations of functional connectivity in schizophrenia. METHODS: The rubber hand illusion was achieved when two paintbrushes simultaneously stroke the hand of the subject hidden from vision by a screen, as well as an artificial hand placed in view of the subject. The rubber hand illusion was assessed with a questionnaire affirming or denying the occurrence of the illusion. RESULTS: Schizophrenic subjects felt the illusion stronger and faster then did normal control subjects. Some rubber hand illusion effects correlated with positive symptoms of schizophrenia but not with negative symptoms. CONCLUSIONS: Altered functional integration of environmental inputs could constitute the basis for erroneous interpretations of reality, such as delusions and hallucinations.

Changes in psychological symptoms during the adjustment of recent immigrants.

In the present study, we sought to compare the number, severity, and frequency of psychological symptoms and the intensity of perceived stressors among immigrants with previously identified positive, negative, or normal patterns of distress. We evaluated 199 recent immigrants from the former Soviet Union to Israel using the Talbieh Brief Distress Inventory (TBDI) and the Perceived Immigration-Related Stressors Scale (PIRSS) with a 1-year follow-up period. As predicted, the number, severity, and frequency of psychological symptoms and the intensity of perceived stress factors vary among immigrants showing different distress patterns. A negative pattern was associated with an increase in the total number, severity, and frequency of distress-related symptoms and persisting cultural-related stress over time. A positive pattern was associated with a reduction in the overall number and severity of symptoms, as well as a decline in the frequency of distress-free symptoms and the intensity of all but informational-related stressors. A normal pattern was characterized by the reduction of distress symptoms within a normal range along with material- and health-related stresses. Our findings confirm the validity of the suggested classification for different patterns of distress and its usefulness in establishing the prognosis for the adjustment of immigrants.

Sudden death in patients receiving clozapine treatment: a preliminary investigation.

The risk of sudden death during clozapine treatment is controversial. The authors present a review of sudden deaths that occurred at Sha'ar Menashe Mental Health Center between January 1991 and August 1997. The number of cases of deceased inpatients was retrieved from the hospital's computerized database and divided into three groups: sudden death, suicide, and disease-related death. Copies of mandatory reports of sudden death filed with the Ministry of Health were obtained, and the corresponding patient records were reviewed. The rates of sudden death, suicide, and disease-related deaths were calculated for clozapine-treated patients (CTPs) during and after treatment and for patients treated with other psychiatric agents (non-CTPs). Among 561 CTPs, there were 4 sudden deaths during treatment, 2 sudden deaths after treatment, 2 suicides during treatment, and 2 disease-related deaths during treatment. Among 4918 non-CTPs, there were 14 sudden deaths, 5 suicides, and 86 disease-related deaths, all of which occurred during treatment with other psychiatric agents. CTPs who experienced sudden death were 10.37 years younger and healthier than non-CTPs who experienced sudden death. The sudden death rate was 3.8 times higher for CTPs than for non-CTPs, whereas the rate of disease-related death was 5 times higher for non-CTPs than for CTPs. Contrary to expectations, the rate of suicide among patients currently receiving clozapine in this sample was 3.6 times higher than among non-CTPs. Because CTPs who experienced sudden death were also younger and healthier, it seems that treatment with clozapine may present a greater risk for sudden death than treatment with other psychiatric medications. The limited number of sudden death cases and deaths from other causes should be noted so that these findings are considered with caution.

Paroxetine binding in aggressive schizophrenic patients.

Decreased central serotonergic activity has been associated with aggressive behavior in humans and animals. Whether or not this phenomenon is related to current aggression or to aggressive tendency is debatable. [3H]paroxetine binding in blood platelets represents the activity of serotonin peripheral binding sites. We investigated a possible association between [3H]paroxetine binding in blood platelets and current aggression or homicidal history in schizophrenic patients. Blood platelets of 11 aggressive schizophrenic patients were assayed for [3H]paroxetine binding in blood platelets and compared to findings in 15 non-aggressive schizophrenic patients, 15 presently non-aggressive schizophrenic patients with homicidal history, and 15 healthy volunteers. Clinical evaluation was performed using the Positive and Negative Syndrome Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scale. B(max) of [3H]paroxetine binding in blood platelets of currently aggressive schizophrenic patients was significantly higher than that in platelets of non-aggressive schizophrenic patients, presently non-aggressive patients with homicidal history and healthy volunteers. No difference was found between the last three study groups. No significant correlation was found between scores of all rating scales and the investigated biochemical parameters. An association was found between current aggression among schizophrenic patients and high B(max) values of [3H]paroxetine binding in blood platelets. This association is probably related to present state of aggression rather than to tendency towards aggression.

Somatization in an immigrant population in Israel: a community survey of prevalence, risk factors, and help-seeking behavior.

OBJECTIVE: Knowledge about the frequency, severity, and risk factors of somatization (somatic manifestations of psychological distress) among immigrants is limited. The authors examined somatic distress in an immigrant population in Israel, explored its relationship with psychological distress symptoms and health-care-seeking behavior, and determined its correlation with the length of residence in Israel. METHOD: Two reliable and validated self-report questionnaires, the Brief Symptom Inventory and the Demographic Psychosocial Inventory, were administered in a cross-sectional community survey of 966 Jewish immigrants from the former Soviet Union who had arrived in Israel within the previous 30 months. RESULTS: The 6-month prevalence rate for somatization was 21.9% and for psychological distress, 55.3%. The current rate of co-occurrence of somatization and psychological distress was 20.4%. The most common physical complaints were heart or chest pain, feelings of weakness in different parts of the body, and nausea. Somatization was positively correlated with the intensity of psychological distress and with help-seeking behavior during the 6 months preceding the survey. Women reported significantly more somatic and other distress symptoms than men. Older and divorced or widowed individuals were more likely to meet the criteria for somatization. Within the first 30 months after resettlement, longer length of residence was associated with higher levels of somatization symptoms. CONCLUSIONS: Somatization is a prevalent problem among individuals in cross-cultural transition and is associated with psychological distress; demographic characteristics such as gender, age, marital status, and duration of immigration; self-reported health problems; and immigrants' help-seeking behavior.

Suicidal ideation and suicide attempts among immigrant adolescents from the former Soviet Union to Israel.

OBJECTIVE: A community survey was conducted to examine suicidal ideation and suicide attempts, behavior problems, psychological distress, social support, and adjustment difficulties in a sample of adolescents. METHOD: Four hundred six Russian-born Jewish immigrants to Israel, aged 11 to 18 years, were selected to match the age and sex distribution of the total immigrant adolescent population. Two indigenous samples of Jewish adolescents in Russia (n = 203) and in Israel (n = 104) were matched with immigrants for comparison. Parameters of interest were measured with self-administered questionnaires. RESULTS: The 6-month prevalence rate of suicidal ideation in the immigrant sample (10.9%) was significantly higher than that for Russian controls (3.5%) but not for Israeli natives (8.7%). There were few gender differences in suicidal ideation and suicide attempts. Older adolescents reported suicidal ideation 2 times more frequently than their younger counterparts. Suicide ideators scored significantly higher than nonideators on all scales of psychological distress and behavior problems. They rated higher sources of immigration difficulties concerning language, physical health, personality characteristics, and family problems but had less socioeconomic and intercultural problems of migration and lower social support from the family but not from other sources. CONCLUSIONS: Results clearly support the migration-convergence hypothesis of suicide risk among adolescents.

Psychological distress through immigration: the two-phase temporal pattern?

A large community sample, cross-sectional and in part longitudinal design, and comparison groups was used to determine the timing of psychological distress among immigrants. A total of 2,378 adult immigrants from the former Soviet Union to Israel completed the self-administered questionnaire Talbieh Brief Distress Inventory. The aggregate levels of distress and six psychological symptoms--obsessiveness, hostility, interpersonal sensitivity, depression, anxiety, and paranoid ideation--were compared at 20 intervals covering 1 to 60 months after resettlement. The level of psychological distress was significantly higher in the immigrants than that of Israeli natives but not in the potential immigrant controls. A two-phase temporal pattern of development of psychological distress was revealed consisting of escalation and reduction phases. The escalation phase was characterized by an increase in distress levels until the 27th month after arrival (a peak) and the reduction phase led to a decline returning to normal levels. The 1-month prevalence rate was 15.6% for the total sample, and for highly distressed subjects it reached 24% at the 27th month after arrival, and it declined to 4% at the 44th month. The time pattern of distress shared males and females, married and divorced/widowed (but not singles), as well as subjects of all age groups (except for immigrants in their forties). The two-phase pattern of distress obtained according to cross-sectional data was indirectly confirmed through a longitudinal way. Claims of early euphoric or distress-free period followed by mental health crisis frequently referred to in the literature on migration was not supported by this study.

Possible precipitants of psychiatric hospitalization in patients with major depression: results from the Jerusalem Collaborative Depression Project.

In spite of substantial advances in the treatment of major depression by pharmacotherapy and other means, a significant number of depressed patients require hospitalization. In the context of the Jerusalem Collaborative Depression Project, possible precipitants of psychiatric hospitalization were sought in a cohort of patients (n = 107) who were admitted to hospitals in the Jerusalem area during a 14-month period because of a depressive episode. The patients fulfilled DSM III-R criteria for major depression, single or recurrent; bipolar 1 disorder, depressed or mixed; bipolar 2, depressed. The cohort encompassed more than two thirds of potential subjects admitted during this period with the ICD-9 equivalents of the specified diagnoses (as reported to the Israel Ministry of Health National Psychiatric Case Register) and were similar to the entire potential population in terms of their diagnostic breakdown. The patients underwent extensive socio-demographic and clinical evaluation that included detailed documentation of treatment received prior to hospitalization. Notwithstanding the absence of a comparison group of depressed patients who were not hospitalized, a number of potential precipitants were identified. These included older age (55.2% > 60 years, 20.6% > 70 years), immigration to Israel during the preceding 5 years (34.7%), concomitant physical illness (60%) which was associated with moderate to severe disability in 41% and poor quality of antidepressant pharmacotherapy prior to hospitalisation (only 24.3% received an adequate trial of antidepressant medication). Further evaluation of these and other potential factors could facilitate targeting of patient groups at particular risk for hospitalization and reduce the need for it.

Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia.

The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.