SCHIZOPHRENIA***
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;
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;
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,
Long-Term Memory Deficits in Schizophrenia: Primary or
Secondary Dysfunction?
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.
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 symptoma