Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.

Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).

Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements.

BACKGROUND: The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. METHOD: The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. RESULTS: The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. CONCLUSIONS: These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia.

Attitudes of psychology students to depression and its treatment: Implications for clinical practice.

Stigma and mental health literacy affect access to and quality of treatment of major depression. Though mental health professionals seem better able to recognize major depression than the general public, they often hold similarly stigmatizing attitudes towards people suffering from the disorder. These attitudes are shaped jointly by the public stigma attached to mental illnesses as well as by the content and delivery of mental health professionals' undergraduate training. In line with this, the present study aimed to explore psychology students' ability to recognize major depression, their attitudes towards the disorder, and their views surrounding helpfulness of various interventions. A random sample of 167 undergraduate students was recruited from the psychology department of one public university in Athens. During one university hour, students were administered a vignette describing a woman fulfilling the DSM-IV criteria for major depression. A self-report questionnaire exploring students' recognition abilities, attitudes to depression and views on the helpfulness of various treatment modes was also administered. In total, 80.2% of students correctly recognized major depression from the vignette. Concerning their attitudes, students were unsure about the illness and ambivalent towards the person who suffers from it. With regard to available treatments for depression, students considered discussion with a friend to be the most helpful intervention. Counseling, cognitive behavioural therapy and psychoanalysis were also viewed in a positive light. On the contrary, antidepressants were not deemed helpful by most students. Finally, recognition of as well as attitudes towards depression and its treatments seemed to improve during the second year of undergraduate study; however they remained unchanged thereafter. Consistent with these, psychology students seem to have only a rudimentary knowledge on depression, that cannot not be qualified as mental health literacy. The core misconception espoused pertains to the view that major depression is not a medical illness; a finding which can also be interpreted in light of the lingering controversy on the medicalization of normal sadness and human predicament. The clinical implications of these findings are substantial. Mental health professionals-educators should reflect on their own beliefs and attitudes towards depression, as they may convey stigmatizing messages to their students and thus perpetuate the stigmatization of the illness. Concomitantly, psychology students' attitudes to depression and its treatment might render them incapable of understanding their patients, responding to their needs and providing them with appropriate help, while they may hinder their effective collaboration with psychiatrists.

Suicide in cyprus 1988-1999.

Suicide is a universally observed human behavior related to bio-psychological, social and cultural factors. The aim of the present study was to examine suicide in Cyprus, an island that has known many civilizations and cultures. All completed suicide cases in the Christian population of Cyprus during the years 1988-1999 were included in the study and they were analyzed according to age, gender, reported reasons for suicide and suicide methods. The main results indicate that: 1. The mean age-standardized suicide rate is the lowest in Europe, in males (3.08/100,000) and also in females (1.05/100,000). 2. Mean suicide rates increase significantly with age in males only. 3. Female suicide rates are highest in the 15-24 age group. 4. Statistically significant rising trends of male and female suicide rates in the all-ages group. 5. Suicide methods were mostly violent. Among males, the most common methods were poisoning, firearms-explosives, and hanging, while in females, jumping, hanging and poisoning. 6. Mental disorders, physical illness, interpersonal and financial problems were the main reported reasons for suicide. The epidemiological characteristics of suicide in Cyprus might be attributed to a combined effect of social and cultural factors and probably reflect influences from countries to which Cyprus is ethnically, historically or geographically related.

Bipolar disorder and self-stigma: A comparison with schizophrenia.

AIM: Even though numerous studies have focused on the effects of self-stigma on patients with schizophrenia, little is known about self-stigma of patients with bipolar disorder (BD). In this study, a self-administered scale of self-stigmatising attitudes of patients with BD and schizophrenia was used to explore these attitudes, examine the potential differences between the two groups and study the factors that influence stigma within groups. METHODS: Self-stigma of 120 patients with schizophrenia and BD was assessed with the Self-stigma Questionnaire (SSQ) and the Stigma Inventory for Mental Illness (SIMI). Presence of clinical symptoms, overall functioning and level of self-esteem were also evaluated. RESULTS: Self-stigma is present in both groups but differs in its intensity. Patients with BD experience self-stigma in a lesser degree without affecting their social life or overall functioning. Patients with schizophrenia adopt more intense self-stigmatising attitudes leading to social exclusion and lower level of overall functioning. LIMITATIONS: The results are limited by the small sample size, whereas the inclusion of other questionnaires would broaden our insight to self-stigma. CONCLUSIONS: Self-stigma has a direct effect on overall functioning of patients with BD and schizophrenia tampering the clinical outcome of therapeutic interventions. Therefore, it should be incorporated in every treatment plan and be addressed as a clinical symptom of the mental illness.

Histochemical changes in the blood cells of schizophrenic patients under pimozide treatment.

Chromatin structure and nucleohistone pattern were investigated histochemically in the neutrophils of 11 schizophrenics and 16 healthy controls. Compared to controls, all schizophrenic parents prior to medication showed a distinctly different histochemical pattern consisting of increased concentration and abnormal distribution of nucleohistones. This pattern has been attributed to an increase of arginine-rich histones in schizophrenics. Pimozide administration exerted a normalizing effect on the nucleohistone distribution pattern. These findings further support our view that genomic expression abnormalities may be related to schizophrenic illness.

Physical activity and plasma cyclic adenosine monophosphate levels in manic-depressive patients and healthy adults.

Intense exercise for one hour induced a significant increase in plasma cyclic adenosine monophosphate (cAMP) in 5 healthy volunteers. In 44 manic-depressive patients, cAMP levels correlated more strongly with mood ratings than with activity scores. The authors conclude that physical activity is one of the factors which contribute to changes of cAMP levels in affective illness.

GABA-A receptor beta3 and alpha5 subunit gene cluster on chromosome 15q11-q13 and bipolar disorder: a genetic association study.

There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA-A receptor alpha5 subunit gene locus (GABRA5) on chromosome 15q11-of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor beta3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM-IV and ICD-10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy-Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA-repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA-repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease.

Association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) and bipolar affective disorder.

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness.

Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients.

A number of immunological parameters were studied in 82 DSM-III-R diagnosed schizophrenic patients (53 first drug-naive and 29 medicated chronic patients) as well as 62 healthy blood donors. The serum levels of interleukin-2 (IL-2), interleukin-1 beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) were measured and correlated with cellular immunity, as assessed by the autologous mixed lymphocyte reaction (AMLR). T lymphocyte subsets were also examined. The above immune parameters were reassessed in a subgroup of 11 first-episode, drug-naive patients 1month after neuroleptic medication. IL-2 serum levels were significantly lower, and IL-1beta and TNF-alpha were significantly higher in schizophrenic patients compared with healthy donors (P<0.001); no significant difference was observed between the two patient groups (medicated and not medicated). Abnormal cytokine serum levels were associated with decreased AMLR responses in vitro. Increased percentages of activated CD4+ and CD16+ natural killer cells, as well as cells expressing ICAM-1 adhesion molecules and IL-2 specific receptors, were detected in the patients. Immunophenotype studies revealed a higher percentage of cells expressing IL-2 receptors in medicated chronic schizophrenic patients compared with drug-naive patients. The abnormal cytokine production in vivo, along with the low AMLR responses in vitro, and the high percentage of activated CD4+ lymphocytes presented in this study suggest alterations in the immune system of schizophrenic patients (medicated or not medicated) consistent with immune activation.

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder.

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.

An experimental antidepressant increases REM sleep.

1. An experimental antidepressant was studied through sleep laboratory recordings, psychoendocrinological tests and clinical measurements in terms of its efficacy, side effects and effects on sleep. 2. The design included a four-week drug administration period, preceeded and followed by a one week placebo period. 3. In the presence of antidepressant efficacy, the drug did not disturb sleep induction and maintainance. 4. The only effect on sleep stages was an increase of REM sleep during the short-term drug administration period which is contrary to the REM supressant effect of most antidepressants. 5. This finding suggests that REM supression and antidepressant efficacy are not necessarily related. 6. Further, given that the only known action of the drug is its inhibitory effect on GABAergic transmission, one can speculate that GABA mechanisms may be involved in REM sleep modulation.

Growth hormone secretion during sleep in male depressed patients.

1. Growth hormone (GH) secretion during sleep was studied in ten male patients with major depression according to DSM III and eight normal controls. 2. Samples were collected through a continuous blood withdrawal pump while sleep was recorded in the laboratory. 3. The results showed a marked decrease in the GH secretion mainly during the first three hours of sleep in depressed patients as compared to normal controls. DST and TRH tests were also administered to the same patients but no correlation was observed between a positive test and a blunted GH secretion, suggesting that the various neuroendocrinological disturbances do not coexist in all depressed patients. 4. This disturbance in GH secretion during sleep, along with reduced slow wave sleep (SWS), gives support to the theory that GHRH is the common stimulus of SWS and GH release and that the ratio of GHRH and its counterpart CRH plays a major role in the pathophysiology of disturbed endocrine activity during sleep in depression.

Effects of methysergide and ritanserin on the prolactin and thyrotropin responses to TRH in depressed patients.

Despite extensive study of the effects of various pharmacological agents on the thyrotropin (TSH) and prolactin (PRL) responses to TRH challenge, the effect of serotoninergic agents remains inconclusive. We studied the effect of the serotonin antagonists methysergide (non-selective 5-HT1/5-HT2 blocker with dopaminergic properties) and ritanserin (selective 5-HT2 blocker) on the TSH and PRL responses to TRH stimulation in two groups of medication-free female depressed patients in a double-blind, within-subject design. Methysergide was found to decrease significantly the PRL response to TRH, while ritanserin had no effect. Neither compound influenced the TSH response. Results suggest that 5-HT2 mechanisms do not mediate the PRL and TSH responses to TRH challenge in depression. The reduction in PRL observed after methysergide is probably due to either 5-HT1 or dopaminergic mechanisms.

Early adolescent cannabis exposure and positive and negative dimensions of psychosis.

AIMS: To investigate the effect of exposure to cannabis early in adolescence on subclinical positive and negative symptoms of psychosis. DESIGN: Cross-sectional survey in the context of an ongoing cohort study. SETTING: Government-supported general population cohort study. PARTICIPANTS: A total of 3500 representative 19-year olds in Greece. MEASUREMENTS: Subjects filled in the 40-item Community Assessment of Psychic Experiences, measuring subclinical positive (paranoia, hallucinations, grandiosity, first-rank symptoms) and negative psychosis dimensions and depression. Drug use was also reported on. FINDINGS: Use of cannabis was associated positively with both positive and negative dimensions of psychosis, independent of each other, and of depression. An association between cannabis and depression disappeared after adjustment for the negative psychosis dimensions. First use of cannabis below age 16 years was associated with a much stronger effect than first use after age 15 years, independent of life-time frequency of use. The association between cannabis and psychosis was not influenced by the distress associated with the experiences, indicating that self-medication may be an unlikely explanation for the entire association between cannabis and psychosis. CONCLUSIONS: These results add credence to the hypothesis that cannabis contributes to the population level of expression of psychosis. In particular, exposure early in adolescence may increase the risk for the subclinical positive and negative dimensions of psychosis, but not for depression.

Effect of moclobemide on clinical and neurochemical variables in depressed patients (preliminary findings).

In this paper the preliminary results from an ongoing investigation on the effect of the MAO-A inhibitor moclobemide on clinicolaboratory variables (antidepressant effect, platelet MAO activity, urinary MHPG and 5-HIAA excretion, plasma prolactin and growth hormone levels and TSH response to TRH) are reported. From the total of 18 patients, 10 (2 males and 8 females) responded favourably (reduction in the HDRS 50% or more) to the treatment. Urine MHPG excretion significantly (p less than 0.001) decreased during treatment, while 5-HIAA secretion showed a less pronounced decrease (p less than 0.05). Plasma PRL and GH remained unchanged, while the TSH-response to TRH increased significantly (p less than 0.025) after 4-week treatment. A significant correlation was found between MHPG pretreatment values and treatment outcome.

Therapy and prevention of affective illness by total sleep deprivation.

The therapeutic effect of total sleep deprivation (SD) given twice a week, for 4 weeks, was investigated in 16 drug-free patients with major affective disorders. The response was excellent in five patients, satisfactory in three and minimal in eight patients. Six of these patients were treated prophylactically once a week, and four had an excellent response. Additionally, out of five normothymic drug-free patients with affective illness treated prophylactically with SD, without prior therapeutic SD treatment, three had an excellent response. The majority of responders were rapid cycling patients. This method is worth applying to patients resistant to classical treatment.

Linkage of mood disorders with D2, D3 and TH genes: a multicenter study.

BACKGROUND: It has been suggested that the dopaminergic system is involved in the pathophysiology of mood disorders. We conducted a multicenter study of families with mood disorders, to investigate a possible linkage with genes coding for dopamine receptor D2, dopamine receptor D3 and tyrosine hydroxylase (TH). METHODS: Twenty three mood disorder pedigrees collected within the framework of the European Collaborative Project on Affective Disorders were analyzed with parametric and non-parametric linkage methods. Various potential phenotypes were considered, from a narrow (only bipolar as affected) to a broad (bipolar+major depressive+schizoaffective disorders) definition of affection status. RESULTS: Parametric analyses excluded linkage for all the candidate genes, even though small positive LOD (Limit of Detection) scores were observed for TH in three families. Non-parametric analyses yielded negative results for all markers. CONCLUSION: The D2 and D3 dopamine receptors were, therefore, not a major liability factor for mood disorders in our sample, whereas TH may play a role in a subgroup of patients.

Relapse prevention in schizophrenia: attitudes of neurologists-psychiatrists.

The overall high relapse rates observed in schizophrenia are attributed to several causes. One important factor influencing satisfactory prevention of relapse is the lack of consistent treatment strategies among medical doctors, especially neurologists-psychiatrists. Nearly one-third of the members of the Hellenic Society of Neurology and Psychiatry were asked to fill in anonymously a structured questionnaire on their treatment attitudes and prescribing tactics regarding schizophrenic patients both after the first schizophrenic episode and after multiple episodes. The majority of Greek neurologists-psychiatrists seem to adopt prescribing habits that approximate the current international standards for prevention of schizophrenic relapse. Their attitudes regarding the treatment and prevention of relapse for the first schizophrenic episode and first relapse are determined from multiple factors. These are: the expected relapse rates after the first episode, the expected prevalence of extrapyramidal side effects following a long-term neuroleptic treatment, the patient's expected treatment compliance after the first episode, the doctor's experience with treating schizophrenics, and lastly the knowledge of current literature on the topic. These results point to the need for continuing education, especially of the younger mental health professionals and those working in the private sector, addressing the issue of the actual risk of developing side effects from the treatment. In due course, benefits could result for everyday psychiatric practice and the patients' compliance with treatment.