Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4).

The dopamine D4 receptor (DRD4), a well-characterized, polymorphic gene, is an attractive candidate for contributing risk to disordered eating and anorexia nervosa (AN). We tested association using UNPHASED for 5 DRD4 polymorphic loci, 3 promoter region SNPs (C-521T, C-616G, A-809G), the 120 bp promoter region tandem duplication and the exon III repeat, in 202 AN trios and 418 control families. Since perfectionism characterizes AN, we tested these five loci for association with the Child and Adolescent Perfectionism Scale (CAPS) in the AN and control groups. Single locus analysis showed significant association between the 'C' C-521T allele and AN. Haplotype analysis also showed significant association, particularly a 4-locus haplotype (exon III&120 bp repeat&C-521T&A-809G). Association was also observed between DRD4 and CAPS scores both for AN and control subjects. The insulin-like growth factor 2 (IGF2) and the arginine vasopressin 1a receptor (AVPR1a), previously shown to be associated with disordered eating, were also associated with CAPS scores. Three genes associated with AN were also associated with perfectionism. Personality traits are potential endophenotypes for understanding the etiology of eating disorders and one of the several pathways to eating pathology may be mediated by the impact of DNA sequences on perfectionism.     

Angiotensin converting enzyme gene insertion/deletion polymorphism: Case‐control association studies in schizophrenia,major affective disorder,and tardive dyskinesia and a family‐based association study in schizophrenia

Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined. © 2002 Wiley‐Liss, Inc.     

Cerebral perfusion after a 2-year remission in major depression

Although patients suffering from major depression respond to antidepressant treatment within several weeks, full reinstatement of premorbid capabilities requires much longer. Nevertheless, most research in major depression seeking the pathophysiological correlates of remission has focused upon the acute post-treatment period. Brain imaging research offers no exception. We have recently shown that cerebral perfusion in depressed patients responding to 6-wk antidepressant medication increases in parieto/cerebellar regions and becomes similar to that of healthy control subjects. We now present technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (99mTc-HMPAO SPECT) data collected from 11 of these patients 2 years in remission. Images were analysed using Statistical Parametric Mapping. After 2 years, perfusion normalization found immediately after treatment was maintained, with further increases in frontal and decreases in parieto/cerebellar regions. These findings suggest that perfusion increases in parieto/cerebellar regions may be involved in acute response to treatment whereas increases in frontal regions may be related to its consolidation.     

Regulation of 5-hydroxytryptamine1A receptor function in rat hippocampus by short- and long-term administration of 5-hydroxytryptamine1A agonist and antidepressants.

Single s.c. injections of the 5-hydroxytryptamine (5-HT)1A receptor agonists buspirone at 4 mg/kg, 8-hydroxy-2-(di-n-propylamino)tetralin at 1 or 4 mg/kg or ipsapirone at 10 mg/kg did not affect 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. However, a single injection of buspirone at 8 mg/kg, and daily injections of each of the agonists for 8 days, resulted in a reduction in the degree of enzyme inhibition by 5-HT. Chronic administration of the antidepressants fluoxetine, zimelidine and maprotiline by i.p. injections at 15 mg/kg for 3 weeks also resulted in a decreased degree of enzyme inhibition. Chronic iprindole at the same dose had no effect. It is concluded that the antidepressant-like properties of 5-HT1A receptor agonists may be mediated partly by a postsynaptic action at the level of serotonergic second messenger transduction in the hippocampus.     

Studies on the role of brain cholinergic systems in the therapeutic mechanisms and adverse effects of ECT and lithium

Brain cholinergic systems are thought to play an important role in memory function and mood regulation. Electroconvulsive therapy (ECT) and lithium (Li) have substantial therapeutic effects on abnormal mood and may adversely affect cognitive processes. The effects of chronic electroconvulsive shock (ECS) and Li administration on brain muscarinic cholinergic receptors (MCR), and on functional correlates of altered brain cholinergic activity, were therefore studied. ECS reduced MCR number in the cerebral cortex and diminished cataleptic responses to the muscarinic agonist, pilocarpine. MCR down-regulation may have therapeutic implications in depression which has been putatively linked to central cholinergic supersensitivity. Alternatively, ECS effects on brain cholinergic function may be involved in the pathogenesis of ECT-induced memory deficits. Both ECS-induced MCR subsensitivity and a clinically equivalent model of ECT-induced anterograde amnesia were not demonstrable after a single ECS, were cumulatively induced by repeated treatments, and may be reversible by administration concurrently with ECS of a muscarinic antagonist. Li increased MCR binding marginally in the cortex and hippocampus and significantly in the corpus striatum. Li substantially enhanced cataleptic and hypothermic responses to pilocarpine. Combined Li-scopolamine pretreatment had an additive effect on these cholinergically mediated responses. Effects of Li and scopolamine on MCR binding were not additive, a finding supporting the conclusion that Li enhances brain cholinergic function by its presynaptic effects on acetylcholine turnover and release. Possible implications for the therapeutic mechanisms and adverse effects of Li are considered.