Frank Fleming

Weight gain associated with the −759C/T polymorphism of the 5HT2C receptor and olanzapine

Weight gain from atypical antipsychotic use has become a significant problem. Recent reports have liked the −759 polymorphism of the 5HT2C receptor and obesity as well as weight gain from chlorpromazine, risperidone, and clozapine.

Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid

We describe the results of our follow-up magnetic resonance imaging (MRI) study of underweight patients with anorexia nervosa, using rigorous methodology to control for head position across time. All subjects first underwent an initial scan and rescan to verify that our computerized three-dimensional co-planar grid method for volume measurement was reliable and accurate, regardless of head positioning. After a period of several months, subjects had a follow-up scan to assess for changes that may have occurred following significant weight gain. Ventricular and total brain volume measurements from the initial scans were compared with the scans from an age- and sex-matched normal control group to determine whether we could replicate previous findings of ventricular enlargement compared with controls and whether brain volume is reduced compared with controls. Anorexic subjects had significantly larger ventricles when compared with normal controls but did not differ significantly in total brain volume. Using a repeated measures analysis of variance, a priori contrasts compared the initial/rescan pair volumes with each other and the initial/rescan pair volumes with the follow-up volume. These analyses showed that ventricular and total brain volumes derived from the initial/rescan pair were nearly identical, but that at follow-up ventricular volume decreased significantly and total brain volume increased significantly after weight gain.

Influence of ZNF804a on brain structure volumes and symptom severity in individuals with schizophrenia.

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.

Effect of Antipsychotic Withdrawal on Negative Symptoms in Schizophrenia

Although it is generally accepted that antipsychotic treatment improves the negative symptoms of schizophrenia in the context of improvement of positive symptoms, exactly how and to what extent they effect “primary” negative symptoms remains controversial. Antipsychotic treatment may reduce only those negative symptoms secondary to positive or depressive symptoms, and may have minimal, if any effect, on negative symptoms that represent a primary psychopathological trait manifestation of schizophrenia. In an effort to further examine this issue, we prospectively assessed negative, positive, depressive, and extrapyramidal symptoms following the discontinuation of antipsychotic medication. Fifty-nine DSM III-R schizophrenic patients underwent a three-week drug wash as part of our neuroimaging protocols. We assessed psychopathological status and adverse effects utilizing various rating instruments (i.e., Scale for Assessment of Positive Symptoms [SAPS], Scale for Assessment of Negative Symptoms [SANS], Hamilton Rating Scale for Depression, and Simpson-Angus Extrapyramidal) at baseline and weekly during this three-week period. Negative symptoms, as measured by the SANS, worsened significantly during the three-week drug wash. Positive symptoms showed a less consistent change with symptoms of disorganization worsening and with psychotic symptoms remaining the same. The changes in negative symptoms during the drug-free period were correlated with the changes in psychosis and disorganization, but not with changes in depression or extrapyramidal side effects. We were not able to substantiate if the worsening in negative symptoms was a direct result of the worsening of positive symptoms or if they were changing simultaneously, but independent of each other.