Schizophrenia as a Complex Trait: Evidence From a Meta-analysis of Twin Studies

Patrick F. Sullivan, MD, FRANZCP; Kenneth S. Kendler, MD; Michael C. Neale, PhD

Arch Gen Psychiatry. 2003;60:1187-1192.

            Context  There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used.  Objective  To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data.  Data Sources  We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches.  Study Selection  Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment.  Data Synthesis  By using a multigroup twin model, we found evidence for substantial additive genetic effects—the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia—joint estimate, 11% (95% confidence interval, 3%-19%).  Conclusions  Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.



Differences and Similarities in Insular and Temporal Pole MRI Gray Matter Volume Abnormalities in First-Episode Schizophrenia and Affective Psychosis

Kiyoto Kasai, MD; Martha E. Shenton, PhD; Dean F. Salisbury, PhD; Toshiaki Onitsuka, MD, PhD; Sarah K. Toner, BA; Deborah Yurgelun-Todd, PhD; Ron Kikinis, MD; Ferenc A. Jolesz, MD; Robert W. McCarley, MD

Arch Gen Psychiatry. 2003;60:1069-1077.

            Context  Whether psychoses associated with schizophrenia and affective disorder represent manifestations of different disorders or the same disorder is an important but unresolved question in psychiatry. Results of previous volumetric magnetic resonance imaging investigations indicate that gray matter volume reductions in neocortical regions may be specific to schizophrenia.  Objective  To simultaneously evaluate multiple olfactocentric paralimbic regions, which play crucial roles in human emotion and motivation, in first-episode patients with schizophrenia and affective psychosis.  Design  A cross-sectional study using high–spatial resolution magnetic resonance imaging in patients with schizophrenia and affective psychosis at their first hospitalization.  Setting  Inpatient units at a private psychiatric hospital.  Participants  Fifty-three first-episode patients, 27 with schizophrenia and 26 with affective (mainly manic) psychosis, and 29 control subjects.  Main Outcome Measures  Using high–spatial resolution magnetic resonance imaging, the gray matter volumes of 2 olfactocentric paralimbic regions of interest, the insular cortex and the temporal pole, were evaluated.  Results  A bilateral volume reduction in insular cortex gray matter was specific to first-episode patients with schizophrenia. In contrast, both first-episode psychosis groups showed a volume reduction in left temporal pole gray matter and an absence of normal left-greater-than-right asymmetry. Region of interest correlations showed that only patients with schizophrenia lacked a positive correlation between left temporal pole and left anterior amygdala-hippocampal complex gray matter volumes, whereas both psychosis groups were similar in lacking normal positive correlations between left temporal pole and left anterior superior temporal gyrus gray matter volumes.  Conclusions  These partially different and partially similar patterns of structural abnormalities in olfactocentric paralimbic regions and their associated abnormalities in other temporolimbic regions may be important factors in the differential and common manifestations of the 2 psychoses.



Efficacy of Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression

Mauricio Tohen, MD, DrPH; Eduard Vieta, MD, PhD; Joseph Calabrese, MD; Terence A. Ketter, MD; Gary Sachs, MD; Charles Bowden, MD; Philip B. Mitchell, MD; Franca Centorrino, MD; Richard Risser, MS; Robert W. Baker, MD; Angela R. Evans, PhD; Karin Beymer, BS, RPh; Sanjay Dubé, MD; Gary D. Tollefson, MD, PhD; Alan Breier, MD

Arch Gen Psychiatry. 2003;60:1079-1088.

            Background  Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression.  Objective  To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.  Design  Double-blind, 8-week, randomized controlled trial. Setting  Eighty-four sites (inpatient and outpatient) in 13 countries.  Patients  A total of 833 randomized adults with bipolar I depression with a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20.  Intervention  Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86).  Main Outcome Measure  Changes in MADRS total scores using mixed-effects model repeated-measures analyses.  Results  During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and 15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea.  Conclusions  Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.



P300 and Genetic Risk for Schizophrenia

Georg Winterer, MD; Michael F. Egan, MD; Thomas Raedler, MD; Carmen Sanchez, BS; Douglas W. Jones, PhD; Richard Coppola, DSc; Daniel R. Weinberger, MD

Arch Gen Psychiatry. 2003;60:1158-1167. 

            Background  We assessed the suitability of event-related potential frontal and temporoparietal P300 changes as intermediate phenotypes in genetic studies of schizophrenia. We applied a principal component analysis approach based on the notion that P300 abnormalities in siblings of schizophrenic patients may involve a widespread network of relatively weak cortical generators and because an earlier, smaller study that used a topographic analysis of covariance model did not show that localized P300 changes predict risk for schizophrenia.  Methods  P300 changes in 66 schizophrenic patients, 115 healthy siblings of schizophrenic patients, and 89 unrelated controls were studied during a standard auditory oddball paradigm. Principal components were calculated across electrodes, revealing frontal and temporoparietal components for latency and amplitude, respectively. For the frontal and temporoparietal P300 amplitude and latency components, the intraclass correlations (ICCs) between sib-pairs (pairs of unaffected siblings and schizophrenic index patients) and the relative risk ratios () were determined.  Results  Compared with controls, schizophrenic patients and their unaffected siblings showed significant reductions in the temporoparietal P300 amplitude component. Both groups were also characterized by a significantly higher frontal P300 amplitude component. Significant ICCs and increased relative risk ratios were found for the frontal (ICCU = 0.18; P = .04;  = 3.4) and temporoparietal (ICCU = 0.24; P = .01;  = 1.7) P300 amplitude components.  Conclusions  Temporoparietal P300 amplitude reduction and frontal P300 amplitude increase seem to be quantitative phenotypes associated with increased risk of schizophrenia. Both measures may be useful for increasing the statistical power of genetic studies of schizophrenia.



Holthausen, Esther A. E. ; Wiersma, Durk; Sitskoorn, Margriet M.; Dingemans, Peter M.; Schene, Aart H. ; van den Bosch, Robert J.

Long-Term Memory Deficits in Schizophrenia: Primary or Secondary Dysfunction?

Neuropsychology. 17(4):539-547, October 2003.

            Long-term memory impairment is often found in schizophrenia. The question remains whether this is caused by other cognitive deficits. One hundred eighteen first-episode patients were compared with 45 control participants on several memory tasks. The role of processing speed and central executive functions on memory performance was examined with regression analysis for all participants and for patients separately. Deficits were found in general verbal learning performance and retrieval in episodic memory and semantic memory. Processing speed reduced disease-related variance in all memory variables. Coordination, organization of information, and speed of processing were the best predictors for long-term memory deficits in patients. The amount of explained variance, however, is small, especially in general verbal learning performance.



Decrements in Volume of Anterior Ventromedial Temporal Lobe and Olfactory Dysfunction in Schizophrenia

Bruce I. Turetsky, MD; Paul J. Moberg, PhD; David R. Roalf, BA; Steven E. Arnold, MD; Raquel E. Gur, MD, PhD

Arch Gen Psychiatry. 2003;60:1193-1200.

            Context  Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established.  Objectives  To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits.  Design  A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. Setting  Schizophrenia Research Center at the University of Pennsylvania, Philadelphia.  Participants  Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity.  Main Outcome Measures  Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability.  Results  Patients had reduced volumes, relative to cranial size, in left (P = .003) and right (P = .01) perirhinal and left (P = .002) and right (P = .002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance.  Conclusions  Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.



Neuroscience & Biobehavioral Reviews

Article in Press, Corrected Proof

Schizophrenia––an evolutionary enigma?

Martin Brüne

            The term `schizophrenia' refers to a group of disorders that have been described in every human culture. Two apparently well established findings have corroborated the need for an evolutionary explanation of these disorders: (1) cross-culturally stable incidence rates and (2) decreased fecundity of the affected individuals. The rationale behind this relates to the evolutionary paradox that susceptibility genes for schizophrenia are obviously preserved in the human genepool, despite fundamental reproductive disadvantages associated with the disorders. Some researchers have therefore proposed that a compensatory advantage must exist in people who are carriers of these genes or in their first-degree relatives. Such advantages were hypothesised to be outside the brain (e.g. greater resistance against toxins or infectious diseases), or within the social domain (e.g. schizotypal shamans, creativity). More specifically, T.J. Crow has suggested an evolutionary theory of schizophrenia that relates the disorders to an extreme of variation of hemispheric specialisation and the evolution of language due to a single gene mutation located on homologous regions of the sex chromosomes.

               None of the evolutionary scenarios does, however, fully account for the diversity of the symptomatology, nor does any one hypothesis acknowledge the objection that the mere prevalence of a disorder must not be confused with adaptation. In the present article, I therefore discuss the evolutionary hypotheses of schizophrenia, arguing that a symptom-based approach to psychotic disorders in evolutionary perspective may improve upon the existing models of schizophrenia.