Search

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task-associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention-dependent manner in schizophrenia.

Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.

Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the α7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci. © 2001 Wiley-Liss, Inc.

Increased frequency of anticipatory saccades during smooth pursuit eye movements is a potential marker of genetic risk for schizophrenia. Postsaccadic slowing criteria are used to separate anticipatory from other types of saccades. However, the necessary duration of slowed pursuit required to identify an anticipatory saccade remains undetermined. We explored the effect of various postsaccadic slowing duration criteria on effect size in a comparison of younger and older schizophrenic and normal adults. For large anticipatory saccades, varying the duration of postsaccadic slowing criteria did not notably change effect size. For smaller leading saccades, a limited 50-ms duration postsaccadic slowing criterion produced the largest effect size (1.54), and maintained a similar effect size across a broad age range. Leading saccades with a limited duration postsaccadic slowing criteria are a possible marker of genetic risk for schizophrenia.

SUMMARY Initial neurobiological and genetic evi-dence of inheritance of a physiologicalabnormality related to schizophreniahas been obtained, that implicates thea7 nicotinic receptor gene. Bilineal in-heritance may be associated with moresevere, earlier onset illness. Replicationof these findings, identification of themolecular abnormality in the gene, anddetermination of the full role of the ab-normality in psychotic illnesses are nec-essary next steps to determine the roleof this gene in the pathogenesis ofschizophrenia. REFERENCES Adams CE, Stevens KE. 1998. Inhibition of nitricoxide synthetase disrupts inhibitory gatingof auditory responses in rat hippocampus. JPharmacol Exp Ther 287:760–765.Adler LE, Pachtman E, Franks R, Pecevich M,Waldo MC, Freedman R. 1982. Neuro-physiological evidence for a deficit in in-hibitory mechanisms involved in sensorygating in schizophrenia. Biol Psychiatry 17:639–654.Adler LE, Gerhardt GA, Franks R, Baker N,Nagamoto H, Drebing C, Freedman R.1989. Sensory physiology and catechol-amines in schizophrenia and mania. Psychi-atr Res 31:297–309.Adler LE, Hoffer LJ, Griffith J, Waldo M, Freed-man R. 1992. Normalization by nicotine ofdeficient auditory sensory gating in the rela-tives of schizophrenics. Biol Psychiatr 32:607–616.Adler LE, Hoffer LD, Wiser A, Freedman R.1993. Normalization of auditory physiologyby cigarette smoking in schizophrenic pa-tients. Am J Psychiatr 150:1856–1861.Andreasen NC, Paradiso S, O’Leary DS. 1998.“Cognitive dysmetria” as an integrativetheory of schizophrenia: a dysfunction incortical subcortical-cerebellar circuitry?Schizophr Bull 24:203–218.Arolt V, Lencer R, Nolte A, Muller-Myhsok B,Purmann S, Schurmann M, Leutelt J, Pin-now M, Schwinger E. 1996. Eye trackingdysfunction is a putative phenotypic suscep-tibility marker of schizophrenia and maps toa locus on chromosome 6p in families withmultiple occurrence of the disease. Am JMed Genet 67:564–579.Baker NJ, Staunton M, Adler LE, Gerhardt GA,Drebing C, Waldo M, Nagamoto H,Freedman R. 1990. Sensory gating deficitsin psychiatric inpatients: Relation to cate-cholamine metabolites in different diagnos-tic groups. Biol Psychiatr 27:519–528.Berrettini WH, Ferraro TN, Goldin LR, Detera-Wadleigh SD, Choi H, Muniec D, GuroffJJ, Kazuba DM, Nurnberger JI Jr, HsiehWT, Hoehe MR, Gershon ES. 1997. Alinkage study of bipolar illness. Arch GenPsychiatry 54:27–35.Bickford PC, Luntz-Leybman V, Freedman R.1993. Auditory sensory gating in the rathippocampus: modulation by brainstem ac-tivity. Brain Res 607:33–38.Bickford-Wimer PC, Nagamoto H, Johnson R,Adler LE, Egan M, Rose GM, FreedmanR. 1990. Auditory sensory gating in hippo-campal neurons: a model system in the rat.Biol Psychiatr 27:183–192.Bickford PC, Wear KD. 1995. Restoration ofsensory gating of auditory evoked responseby nicotine in fimbria-fornix lesioned rats.Brain Res 705:235–240.Blouin JL, Dombroski BA, Nath SK, LasseterVK, Wolyniec PS, Nestadt G, ThornquistM, Ullrich G, Mcgrath J, Kasch L, LamaczM, Thomas MG, Gehrig C, RadhakrishnaU, Snyder SE, Balk KG, Neufeld K, SwartzKL, Demarchi N, Papadimitriou GN,Dikeos DG, Stefanis CN, Chakravarti A,Childs B, Housman DE, Pulver AE. 1998.Schizophrenia susceptibility loci on chro-mosome 13q31 and 8p21. Nature Genet 20:70–73.Borecki IB, Rao DC, Yaouanq J, Lalouel JM.1990. Serum ferritin as a marker of affectionfor genetic hemochromatosis. HumanHered 40:159–166.Boutros NN, Zouridakis G, Overall J. 1991.Replication and extension of P50 findingsin schizophrenia. Clin Electroencephalogr22:40–45.Breese CR, Adams C, Logel J, Drebing C, Roll-ins Y, Barnhart M, Sullivan B, DeMastersBK, Freedman R, Leonard S. 1997. Com-parison of the regional expression of nico-tinic acetylcholine receptor a7 mRNA and[

Increased frequency of anticipatory saccades during smooth pursuit eye movements is a potential marker of genetic risk for schizophrenia even in the absence of clinical symptomology. The operational definition of anticipatory saccades has often included an amplitude criterion; however, these amplitude criteria have often differed across studies. This study reports on the effect of varying amplitude criteria on the effect size in a comparison of 29 schizophrenic adults and 29 normal subjects during a 16.7°/s constant velocity task. The inclusion of small amplitude anticipatory saccades, with amplitudes of 1–4°, consistently increased effect size (largest effect size = 1.61). The inclusion of large anticipatory saccades, with amplitudes of 4° or greater, had an inconsistent impact on effect size. The separation of anticipatory saccades into leading saccades (anticipatory saccades with amplitude 1–4°) and large anticipatory saccades (amplitude >4°) deserves further exploration.

Childhood-onset schizophrenia is proposed to be associated with increased genetic loading compared with adult-onset schizophrenia because of its earlier age of onset and generally greater severity of symptoms. Diminished suppression of P50 auditory evoked responses to repeated stimuli and elevated anticipatory saccades during smooth pursuit eye movements are markers of genetic risk that are found in members of families with schizophrenia even in the absence of the full clinical disorder and appear to be transmitted in a single gene autosomal dominant fashion. Adult-onset schizophrenia is generally associated with one parent who demonstrates abnormal P50 sensory gating and elevated anticipatory saccades and one parent who is normal on the physiologic measures (i.e., unilineal inheritance). This study investigates whether childhood-onset schizophrenia is similarly unilineal or is associated with the inheritance of genetic risk factors from both parents (i.e., bilineal inheritance). Ten childhood-onset schizophrenic probands and their parents were studied. Their P50 sensory gating and anticipatory saccades were compared with adult-onset schizophrenic probands and their parents. Bilineality, measured as physiological impairment in both parents, occurred more frequently in childhood-onset probands than in adult-onset probands for both P50 sensory gating deficits (60% versus 13%) and elevated anticipatory saccades (60 versus 0%). Additionally, childhood-onset schizophrenic probands performed more poorly than adult-onset probands on the anticipatory saccade measure. This physiological evidence suggests that childhood-onset schizophrenia may be associated with increased genetic loading because of contributions of genetic risk from both parents.

Linkage of a neurophysiological deficit associated with schizophrenia, i.e., the failure to inhibit the auditory P50 response, was previously reported at chromosome 15q14. The marker with the highest pairwise lod score, D15S1360, was isolated from a yeast artificial chromosome containing a candidate gene, the alpha7-nicotinic acetylcholine receptor gene. In the present study, this linkage was further investigated in a subset of the NIMH Genetics Initiative schizophrenia families. These families have not been studied neurophysiologically, as were the families in the original report. Therefore, the DSMIII-R diagnosis of schizophrenia was used as the affected phenotype. Twenty families fulfilled the criteria of at least one sibpair concordant for schizophrenia, along with their two parents or another affected relative outside the nuclear family, available for genotyping. Sibpair analysis showed a significant proportion of D15S1360 alleles shared identical-by-descent (0.58; P < 0.0024). The results further support the involvement of this chromosomal locus in the genetic transmission of schizophrenia.

The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.

In treatment of alcohol dependence, disulfiram is most useful in conjunction with a structured, supervised, aftercare program. However, it has been reported to cause psychiatric side effects and to interact with various psychiatric medications. Many patients with alcohol dependence suffer from other psychiatric disorders and are treated with such psychiatric medications. This paper reviews the pertinent clinical pharmacology of disulfiram and the literature on potential psychiatric complications and drug interactions of disulfiram. At the usual dosage, about 250 mg/day, disulfiram does not appear to increase significantly the risk of psychiatric complications or of psychiatric drug interactions. Therefore, it can be considered a treatment option for patients with alcohol dependence and other psychiatric disorders.