Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation.

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder.

OBJECTIVE: To identify factors associated with substance misuse in first-episode patients with schizophrenia or schizoaffective disorder. METHOD: Twenty-seven patients with a past or current history of substance misuse were compared with 91 patients with no history of misuse on demographic and psychopathological measures before being treated for their first episode of psychosis, and on cognitive measures after 6 months of treatment. RESULTS: There were no statistically significant differences between groups for sex, schizophrenia subtype, marital status, education, family history of schizophrenia, course of illness, age of onset, baseline symptoms, time to treatment response, medication side effects, attention span, memory and executive functioning. However, dual diagnosis patients were found to have a higher parental social class, better premorbid cognitive functioning, higher IQ and better language skills. CONCLUSION: First-episode patients with a history of substance misuse have higher intellectual functioning, which may be associated with higher premorbid socioeconomic status and cognitive functioning.

The internal jugular vein maintains its regional anatomy and patency after carotid endarterectomy: a prospective study.

OBJECTIVE: To validate the authors' published surface landmarks for gaining percutaneous access to the internal jugular vein (IJV), and to determine whether these surface landmarks were altered after neck surgery. SUMMARY BACKGROUND DATA: Carotid puncture and pneumothorax continue to be the most frequent mechanical complications of percutaneous IJV venipuncture, particularly when the anterior or posterior approaches are used. The authors' modified technique of IJV venipuncture was associated with a 0.6% complication rate; notably, there were no instances of carotid artery puncture. Determining the accuracy of this method using duplex ultrasound would enhance the technique's applicability and safety. The authors also hypothesized that previous neck surgery would alter the regional anatomy in relation to these surface landmarks for IJV venipuncture. METHODS: The authors prospectively evaluated 417 IJVs in 209 consecutive patients undergoing carotid duplex imaging before and after carotid endarterectomy (CEA). Patients who had undergone CEA were enrolled to investigate the effect of neck surgery on IJV anatomy. The opposite, nonoperated side of the neck served as a control for each patient. The position of the IJV in relation to the surface landmarks, the mobility of the IJV on neck rotation, and the size, patency, and relation of the IJV to the carotid artery were evaluated. RESULTS: Overall accuracy of the surface landmarks for locating the IJV percutaneously was 99% for the control group and 95% for the CEA group. With neck rotation, the IJV was located in a more lateral position in relation to the landmarks that would significantly reduce its accessibility. After neck rotation, it was also noted that the carotid artery moved behind the jugular vein in 85% of the patients in both groups. The mean size of the vein and its patency were similar in both groups. CONCLUSIONS: Duplex imaging validated the accuracy of the surface landmarks for IJV cannulation and documented the adverse effects of neck rotation. IJV anatomy is not altered after CEA.

Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.

The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-HT1A (HTR1A) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding.

Contingency valuation and preferences of health states associated with side effects of antipsychotic medications in schizophrenia.

The purpose of this study was to investigate the construct validity and the test-retest reliability of the willingness to pay (WTP) method for estimating health state preferences associated with side effects of antipsychotic medication. Ninety-six schizophrenia patients on antipsychotics were asked (1) how much they would be willing to pay to get rid of side effects with 100 percent probability, (2) a standard gamble (SG) question measuring utilities of patient's health state associated with side effects, and (3) their WTP to get rid of side effects based on the utility found with SG. Patients were divided into three groups based on severity of side effects. There was a significant difference between side effect severity groups for (1) the utility associated with side effects (Kruskal-Wallis [K-W] chi-square = 8.48, p = 0.014), and (2) their WTP to get rid of side effects with either 100 percent probability (K-W chi-square = 14.32,p = 0.001) or based on the utility associated with side effects (K-W chi-square = 5.96, p = 0.051). There was a significant correlation between utility and the WTP based on utility (Spearman r = -0.42, p = 0.003). Because of a wide variation in side effects at the 1-month interval, we were unable to assess the test-retest reliability of SG and WTP. Our results suggest that WTP has some construct validity in valuating and measuring preferences of health states associated with side effects of antipsychotics in schizophrenia.

Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.

Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A-1438 A-->G polymorphism in the putative promoter and a silent T-->C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T-->C. 102 allele: chi 2 = 0.02; 1 df, p = .90; genotype: chi 2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: chi 2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: chi 2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: chi 2 = 3.46, 2 df, p = .18; chi 2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.

Manic-depressive illness and linkage reanalysis in the Xq27-Xq28 region of chromosome X.

Inconsistent findings in X linkage studies of manic-depressive illness (MDI) have been ascribed to the presence of phenotypic uncertainties (incomplete penetrance), considerable variation in form and severity of MDI, and the likely presence of phenocopies (or false positives). In order to address some of these issues, previous X linkage data with colour blindness, glucose-6-phosphate dehydrogenase deficiency, and blood coagulation factor IX (F9) markers were reanalysed using a narrow and a broad definition of MDI. Our results confirm the X-linked hypothesis for MDI genetic transmission when controlling for diagnostic variation. The lod score (log of odds ratio) is reduced for a more conservative definition of the disease, but nevertheless remains significant. However, conclusive linkage between the MDI gene and the F9 gene in the Xq27 region is not maintained in our series. Our findings emphasize the need to reanalyse previous genetic data with more sophisticated diagnostic and statistical techniques.

Effects of alprazolam on increases in hormonal and anxiety levels induced by meta-chlorophenylpiperazine.

The effects of alprazolam, a triazolobenzodiazepine, on hormonal and behavioral responses induced by meta-chlorophenylpiperazine (MCPP), a serotonin receptor agonist, were investigated in 10 healthy men. Alprazolam (0.5 mg) or placebo was given 1 hour before MCPP (0.5 mg/kg) or placebo. Cortisol, prolactin, and growth hormone (GH) release, MCPP and alprazolam plasma levels, anxiety level, and panic symptoms were measured over 210 minutes. MCPP was found to increase cortisol, prolactin, GH, and anxiety levels. Alprazolam decreased cortisol and GH levels but had no effect on prolactin. When used in combination with MCPP, alprazolam blunted MCPP-induced cortisol and GH release, and it blocked the anxiogenic effects of MCPP.

Clozapine treatment and its effect on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine.

The effects of clozapine treatment on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine (mCPP) were examined. mCPP and placebo were administered after a 2-week drug-free period and again after 5 weeks of clozapine treatment in nine schizophrenic inpatients. Adrenocorticotropic hormone (ACTH), prolactin, and mCPP levels were measured. Clozapine treatment completely blocked mCPP-induced ACTH and prolactin release suggesting that clozapine blocks serotonin receptors that mediate these hormone responses.

Minireview: Molecular genetics in affective illness.

Genetic transmission in manic depressive illness (MDI) has been explored in twins, adoption, association, and linkage studies. The X-linked transmission hypothesis has been tested by using several markers on chromosome X: Xg blood group, colour blindness, glucose-6-phosphate dehydrogenase (G6PD), factor IX (haemophilia B), and DNA probes such as DXS15, DXS52, F8C, ST14. The hypothesis of autosomal transmission has been tested by association studies with the O blood group located on chromosome 9, as well as linkage studies on chromosome 6 with the Human Leucocyte Antigens (HLA) haplotypes and on Chromosome 11 with DNA markers for the following genes: D2 dopamine receptor, tyrosinase, C-Harvey-Ras-A (HRAS) oncogene, insuline (ins), and tyrosine hydroxylase (TH). Although linkage studies support the hypothesis of a major locus for the transmission of MDI in the Xq27-28 region, several factors are limiting the results, and are discussed in the present review.

Absence of linkage between chromosome 11p15 markers and manic-depressive illness in a Belgian pedigree.

OBJECTIVE: The original finding of genetic linkage in an Old Order Amish pedigree has been contradicted by the results of several subsequent studies. Using the same genetic parameter values, diagnostic criteria, and 11p15 genetic markers as those used to study the initial Amish population, the authors performed a linkage study of a four-generation informative pedigree in Belgium. METHOD: Recombinant DNA technology was used to analyze three markers for the chromosome 11p15 location: the genes for tyrosine hydroxylase (TH) and insulin (INS) and the c-Harvey-ras oncogene (HRAS). Diagnoses of the relatives of a proband with bipolar affective disorder were determined with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version and based on the Research Diagnostic Criteria. Relatives were considered affected if they had bipolar disorder, unipolar disorder, or cyclothymia; a diagnostic hierarchy was developed to include unipolar disorder and cyclothymia in the linkage analysis. RESULTS: Pairwise analyses of the disease locus and each of the three polymorphisms excluded the possibility of close linkage between manic-depressive illness and the three chromosome 11p15 markers. Multipoint linkage analysis combining the information from all three genes also excluded linkage. CONCLUSIONS: The conflict between the original results from the Amish study and the many negative reports on chromosome 11 linkage of manic-depression has been interpreted as indicating genetic heterogeneity, but heterogeneity has not been documented for the 11p15 locus. Conversely, the linkage approach has major drawbacks, so other genetic strategies should also be considered.

Correlates of risk of suicide in violent and nonviolent psychiatric patients.

OBJECTIVE: This study was designed to identify variables that correlate with the risk of suicide in two patient groups that differ mainly in their level of expressed aggression. METHOD: Twenty-eight psychiatric patients with a history of violent behavior who were in a forensic psychiatric facility were tested and compared to 28 psychiatric inpatients without a history of violence who were admitted to a large municipal hospital. Measures used included a battery of self-report questionnaires, with acceptable reliability and validity, that provided indices of risk of suicide, risk of violence, impulsivity, anger, anxiety, and various mood states. RESULTS: The two groups, matched on demographic variables and overall risk of suicide, differed significantly on the measured risk of violence. The two groups showed similar patterns of correlations between risk of suicide and such variables as risk of violence, anger, fear, state and trait anxiety, lack of impulse control, suspiciousness, and rebelliousness. They differed in the correlation between suicide risk and depression. In the nonviolent patients there was a high correlation between risk of suicide and sadness; in the violent patients there was no correlation between these variables. CONCLUSIONS: The low correlation between sadness and risk of suicide in the violent patients, and the low prevalence of affective disorder diagnoses in these patients compared to other patients, suggests that suicidal risk should be managed differently in highly violent patients than in others.

Significance of cocaine history in schizophrenia.

Fifty-one schizophrenic inpatients were divided into two groups, those with and without history of cocaine use, and compared on historical, demographic, cognitive, and psychopathological measures. Patients with a cocaine history were found to be significantly more depressed, less socialized, and more impaired in conceptual encoding and verbal memory, while less disordered in attention. The two groups did not differ in severity of illness or positive and negative syndromes. There were also no differences in control variables such as age, gender, education, intelligence, premorbid adjustment, neuroleptic dose, onset and chronicity of illness, continuity of hospitalization, paranoid subtype, and psychiatric illness in the family. Cocaine history was associated with multiple illicit drug use, but for other substances there was no increased liability for depression or cognitive deficits. The results suggest that the clinical presentation in schizophrenia is significantly associated with prior cocaine experience.

Interrelationships among anxiety, aggression, impulsivity, and mood: a serotonergically linked cluster?

Serotonin abnormalities appear to be related to a variety of psychopathological dimensions such as anxiety, depressed mood, impulsivity, and aggression dysregulation. We hypothesized that the psychopathological dimensions related to serotonin would be significantly intercorrelated since they seem to have a common biological basis. Sixty psychiatric inpatients were examined on a series of psychometric tests measuring suicidality, violence potential, impulsivity, depressive mood, and anxiety. The scores on all of these measures tended to be significantly correlated with one another. These findings support the additional hypothesis that biological markers may be more closely related to basic psychological dimensions than to nosological categories.

Pyramidical model of schizophrenia.

Research and treatment of schizophrenia have been impeded by its heterogeneity and the lack of well-standardized methods for a comprehensive assessment of symptoms, including positive and negative dimensions. To study symptom profiles, therefore, we standardized and administered a well-operationalized 30-item psychiatric symptom scale to 240 schizophrenic inpatients. Principal component analysis suggested a pyramidlike triangular model of uncorrelated but nonexclusive syndromes that encompassed the spectrum of psychopathology. Negative, positive, and depressive features constituted divergent points of a triangular base, and excitement made up a separate vertical axis. Paired syndromes could account for symptoms of the paranoid (positive-depressive), disorganized (positive-negative), and catatonic (negative-depressive) diagnostic subtypes. The transversal positions in this model suggested polarized dimensions in schizophrenia, including a prognostic axis (depression-cognitive dysfunction). The findings imply that (1) negative and positive syndromes show factorial validity and distinction from depression but, alone, are insufficient to accommodate the full diversity of symptoms; (2) schizophrenic subtypes derive from a hybrid between unrelated but co-occurring dimensions that may define the fundamental elements of psychopathology; and (3) the pyramidical model is of heuristic value. The results help to clarify the heterogeneity of schizophrenia and to illuminate the path toward syndrome-specific treatments.

Defense mechanisms in risk of suicide and risk of violence.

This paper reports on an empirical study of defense mechanisms in 60 psychiatric inpatients. Eight defenses--compensation, denial, displacement, intellectualization, projection, reaction formation, regression, and repression--were studied in the context of a two-stage model of suicidal and violent behavior. The results showed that use of regression as a defense differentiated suicidal from nonsuicidal patients, and use of displacement differentiated violent from nonviolent patients. Repression tended to turn aggression inward, and projection and denial turned aggression outward.

Alpha-2-adrenoreceptor binding as a possible vulnerability marker for affective disorders.

The affinity (1/Kd) and density (Bmax) of alpha 2-adrenoreceptors in platelet membranes were studied in patients with major depressed illness (n = 10), affected first-degree relatives (n = 17), nonaffected first-degree relatives (n = 44) and controls (n = 31). The alpha 2 selective antagonist 3H-yohimbine was used as the radioligand. The mean Bmax values of affected subjects (probands and relatives) were significantly lower than those of controls. There was no difference in Kd values between the controls and affected subjects. There was a positive gradient of the mean Bmax values from the groups of probands to affected relatives, unaffected relatives and control subjects. A familial effect of Bmax values between members of the same families confirms a genetic control of alpha-receptor affinity. These results support the hypothesis that the density of alpha 2-adrenoreceptors, evaluated by 3H-yohimbine binding on human platelets, could be a potential vulnerability marker for affective disorder.

REM sleep latency and morbidity risk of affective disorders in depressive illness.

The relationship between rapid eye movements (REM) sleep latency and morbidity risks for affective illness in first-degree relatives of affectively ill probands was investigated in 122 patients suffering from primary major depressive disorder (74 unipolars, 48 bipolars) according to the Research Diagnostic Criteria. Sleep EEG scoring was done blind to the clinical diagnosis of the probands and their relatives, and the evaluation of morbidity risks for affective illness in first-degree relatives was done using Strömgren's method with age correction. A logistic regression analysis was performed to describe the proportion of affectively ill relatives as a function of variables recorded in 122 probands with primary major depression. Our analysis demonstrates an inverse relationship between REM sleep latency and the risk for depressive disorder in the families of affectively ill probands. These results suggest the possibility that common pathophysiological factors may be involved in the hereditary predisposition to affective illness and in the shortening of REM sleep latency in some depressed patients.