andreasen, n. - schizophrenia

7/30/2019 Andreasen, N. - Schizophrenia

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Statistical Manual of Mental Disorders, fourth edition(DSM-IV),4 which describe characteristic symptoms of

schizophrenia. In ICD-10, severe symptoms should have

been present for 1 month, whereas in DSM-IV,

6 months duration is required (ie, including less severe

prodromal and residual symptoms). The DSM-IV criteria

also require deterioration in social and occupational

functioning, specified as dysfunction in work,

interpersonal relations, or self-care. Other diagnoses,

such as a mood disorders with psychotic features, must

be ruled out and symptoms must be shown to be due to

no other medical disorder or drug effect, such as steroid-

induced or amphetamine-induced psychosis (panel).

Once the diagnosis of schizophrenia has become

apparent, social deterioration commonly becomes

prominent and persists after the more severe symptoms

have been controlled with medication. Increasingly,

psychosocial impairment is being studied as an important

outcome measure, and is becoming the focus of

treatment. Outcomes are currently of interest in health-

economics research; probably no other chronic illness

parallels schizophrenia in the potential for poor functional

outcome in the absence of a measurable decrease in

lifespan, which is a substantial burden of morbidity.

Psychiatrists are increasingly recognising the correlation

between negative symptoms and loss of social function

among patients with schizophrenia. Diagnosis of

schizophrenia has, therefore, moved towards emphasis of

negative symptoms.

Negative symptoms are decreases in function or loss of

ability to interact meaningfully with other people and the

environment. Many negative symptoms are cognitive,

such as alogia, avolition, and attentional impairment.

These deficits lead to long-term social and economic

burden because patients cannot maintain productive

employment and role functioning.5 Negative symptoms

are the least likely to improve over the course of illness,

and resulting cognitive dysfunction in the context of these

symptoms is most likely to contribute to unemployment.6

Although research has given greater insights into the

impact of symptoms and the nature of the deficits

associated with schizophrenia, the pathophysiology and

causes are still not clearly understood.

Until the neural and molecular substrates are identifiedand a direct measure of the pathology has been found,

Schizophrenia is a devastating illness. It is characterisedby symptoms such as hallucinations or disorganised

thinking, loss of goal-directed behaviours, and

deterioration in social role functioning. Most commonly,

people who have schizophrenia are unable to continue in

employment or education. Typically, onset of illness

occurs in young adults, when individuals would be

experiencing the most independence and beginning a

productive career. Apart from its impact on individuals,

schizophrenia creates a huge economic burden for

society. A review of health-care expenditures in the UK

showed that 54% of total National Health Service

inpatient costs are attributable to schizophrenia. When

inpatient, outpatient, primary-care, pharmaceutical,

community, and social-services expenses were combined,

an annual total cost of 26 billion was estimated.1 In

vulnerable groups, such as the homeless, the cost of this

illness may be even higher. In a report on hospital-

admission costs among the homeless in New York City,

USA, 806% of admissions were associated with

psychiatric diagnoses, including schizophrenia and

substance abuse.2 The prevalence of schizophrenia is

consistently about 1% throughout the world, which

translates into an enormous burden. As well as the strain

on financial and health-care resources, schizophrenia

leads to social and psychological anguish for patients and

their families.

Diagnosis of schizophrenia

Schizophrenia is a complex medical disorder with diverse

clinical presentations. Several cognitive and emotional

functions are impaired, such as perception

(hallucinations), inferential thinking (delusions),

motivation (avolition), and thought and speech (alogia).

Criterion-based systems have been developed to decrease

the complexity and improve the reliability of diagnosis.

These systems include the International Classification of

Diseases, tenth edition (ICD-10)3 and the Diagnostic and

Schizophrenia

Susan K Schultz, Nancy C Andreasen

SEMINAR

THE LANCET Vol 353 April 24, 1999 1425

Lancet1999; 353: 142530

Mental Health Clinical Research Center, 2911-JPP, Department of

Psychiatry, University of Iowa, 200 Hawkins Drive, Iowa City,

IA 52242, USA (S K Schultz MD, Prof N C Andreasen MD)

Correspondence to: Dr Nancy C Andreasen

(e-mail: [email protected])

Seminar

Schizophrenia is among the most severe and debilitating of psychiatric disorders. Diagnosis is currently by criterion-

based systems, including positive (eg, hallucinations and delusions) and negative (eg, avolition and alogia)

symptoms. The importance of negative symptoms in the course and outcome of the illness is increasingly being

studied. Current research seeks to detect causal mechanisms in schizophrenia through studies of neural connectivity

and function, as well as models of genetic transmission, such as polygenic models of inheritance in genetic

research. Potential genes have been identified that may confer vulnerability to the illness, perhaps in conjunction

with environmental factors. Neuroimaging research with magnetic resonance imaging and positron emission

tomography has investigated differences in volumes and functional dysregulation in specific neural subregions. Areas

studied include the frontal and temporal cortex, the hippocampus, the thalamus, and the cerebellum. Despite these

advances, treatment of symptoms and psychosocial and cognitive impairments remains only partially successful for

many patients.


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diagnosis of schizophrenia relies on observation-based

criteria. Diagnostic criteria improve reliability, enable

standardisation across centres, nationally and

internationally, improve clinical communication, and

facilitate research. However, set criteria may give an

oversimplified and incomplete view of the clinical picture,

discourage comprehensive history-taking, and lead

clinicians and students to believe that knowing the

criteria is sufficient to confer diagnostic expertise. Criteria

should not discourage creative or innovative thinking

about the psychological and neural mechanisms of

schizophrenia. Rather, they should be combined with

symptom-rating scales and with clinical experience to

better define features of this disorder that may respond to

various therapeutic interventions. For negative symptoms

especially, there is a substantial need for the developmentof effective treatments.

Genetic research in schizophrenia

Risk of schizophrenia is higher among family members of

patients than in the general population. Adoption studies

have shown that this increased risk is genetic, with a ten-

fold increase in risk associated with the presence of an

affected first-degree family member. This genetic risk

increases with each affected family member, to nearly

50% when both parents are affected.7 Inheritance of

schizophrenia has largely been studied through

mathematical modelling of pedigrees and twin and

adoption data. The exact nature of the genetic

transmission is unclear and does not follow a simple

recessive or dominant pattern associated with a single

gene. Polygenic models of inheritance, which seem most

consistent with data available to date, postulate that an

additive effect of several genes confers susceptibility to

schizophrenia, and may interact with environmental

factors.

Various environmental factors have been investigated

over the past few decades, including viral exposure,

nutritional deficiencies, and obstetric complications. Such

studies have historically been plagued by recall and

selection biases. In a meta-analysis, however, Geddes and

Lawrie8 reported a pooled odds ratio of 20 for an

association between exposure to obstetric complicatons

and development of schizophrenia. Verdoux andcolleagues9 used data from 11 research groups involving

854 patients with schizophrenia to assess age of onset of

psychosis and obstetric complications. A relation was

seen between age of onset younger than 22 years and a

greater likelihood of complications during birth.

In addition to environmental factors, identification of

genetic mechanisms is complicated by the lack of

biological traits specific to schizophrenia. Despite this

difficulty and the improbability that transmission followssimple Mendelian single-gene inheritance patterns, the

availability of genetic markers based on polymorphisms

has enabled large-scale studies to identify linkage to

specific genes. Researchers have successfully implicated

several different gene regions, such as chromasome 6,10

although studies have been difficult to replicate. Because

of these mixed findings, a meta-analysis assessed all

linkage studies of chromosome 6p markers; pooled

analyses suggested a potential susceptibility locus for

schizophrenia in two 6p marker regionsD6S274 and

D6S285.11 A review of all linkage studies concluded that

the weight of the evidence to date suggests that

chromosomes 6 and 8 may contain susceptibility loci for

schizophrenia, whereas studies implicating chromosomes3, 5, 9, 20, and 22 are less well supported.10

One study involved a genome-wide map, analysed

through an international multicentre study of 269

individuals from 43 pedigrees. Five chromosomal regions

(chromosomes 2q, 10q, 4q, 9q, and 11q) were identified,

involving eight marker locations that suggested possible

linkage.12 These findings were consistent with previous

work that identified possible sites on chromosomes 2 and

11, but did not implicate susceptibility loci on

chromosomes 22q, 6p, and 8p found previously.

Linkage studies are complemented by association

studies of candidate genes, rather than chromosomal

regions. In population-based association studies, the

frequency of a marker is investigated for a specific gene inassociation with the presence of a disorder, compared

with a control sample. Typically the psychiatric diagnosis

is used as the phenotypic expression of illness. Biological

traits correlated with the illness can, however, be used as

other indicators of phenotypic expression. For example, a

specific pathological indicator such as the p50 auditory

sensory gating deficit in schizophrenia may be used to

identify susceptibility loci.13 Other examples include

impaired prepulse inhibition or habituation to the startle

reflex, and eye-tracking and eye-blinking abnormalities.

Phenotypes for schizophrenia can, therefore, be identified

that are not based solely on diagnostic classifications.

Strategies are evolving rapidly, each offering the potential

for new insights into the genetic factors involved in theexpression of schizophrenia.

Neuroimaging of neural substrates

The neural substrates of schizophrenia have been

intensively studied by traditional neuropathology

techniques and neuroimaging. Postmortem studies of

patients with schizophrenia have shown no increase in

degenerative pathology such as that known to occur in

Alzheimers disease.14 The consistent absence of

degenerative pathology (eg, gliosis) suggests that

schizophrenia may result from pathological

neurodevelopmental processes.

The use of magnetic resonance imaging (MRI) has

permitted investigation of whether specific or groups ofregions are affected rather than gross brain abnormalities.

1426 THE LANCET Vol 353 April 24, 1999

Diagnosis of schizophrenia

Symptoms

Two symptoms present for at least 1 month: (positive) delusions,

hallucinations, disorganised speech, disorganised or catatonic

behaviour; (negative) affective flattening, alogia, avolition.

Social dysfunction

One or more areas affected for most of the time since onset (required

by DSM-IV): work, interpersonal relations, self-care; if duringadolescence, failure to reach level of interpersonal, academic, or

occupational achievement.

Duration

Active symptoms of psychosis must persist in absence of treatment:

ICD-10 active symptoms for at least 1 month; DSM-IV active

symptoms for at least 6 months, including prodromal and residual,

(negative or attenuated positive) symptoms.

Exclusion of other disorders

Other diagnoses with psychiatric symptoms must be excluded:

schizoaffective disorder; major depression with psychosis; substance

abuse disorders; medical disorders, such as head injury, cerebral

vasculitis, stroke, dementia.


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A meta-analysis of all studies of brain size confirmed a

difference between patients and controls in brain size and

intracranial volume.15 Another meta-analysis of 40

volumetric MRI studies concluded that regions such as

the amygdala and hippocampus were probably smaller

and volume of the parahippocampus, thalamus, and

superior temporal gyri decreased in patients with

schizophrenia compared with controls.16 The investigators

suggested that a testable hypothesis would be a general

increase in cortical white matter relative to smaller

neurons, which accounts for a decrease in grey-matter

volume. A decrease in frontal-lobe size has also been

found. The prefrontal cortex performs many highercortical functions that are disrupted in schizophrenia (eg,

executive functions, abstract thinking, working memory),

which makes it an attractive candidate for study. Three of

four studies showed decreased frontal size in chronic and

first-episode patients. Negative findings are, however,

also common. Newer techniques have been developed to

measure the total volume of grey matter, white matter,

and cerebrospinal fluid. Most of these studies have shown

a decrease in total volume of brain tissue in schizophrenia,

as well as an increase in cerebrospinal fluid in the

ventricles and on the brain surface.17 A selective decrease

in cortical grey matter has also been seen, although some

studies have found white-matter decreases as well.18

Functional imaging techniques such as positronemission tomography and functional MRI are

increasingly used to explore neural circuits that may be

dysfunctional in schizophrenia. Current thinking about

the mechanisms of schizophrenia, based on functional

MRI, postulates a disruption in distributed functional

circuits rather than a single abnormality in a single brain

region such as prefrontal cortex. No specific group of

regions has yet emerged as the schizophrenia circuit,

but a consensus is developing on some of the nodes that

may be involved. These nodes include various subregions

within the frontal cortex (orbital, dorsolateral, medial),

the anterior cingulate gyrus, the thalamus, several

temporal-lobe subregions, and the cerebellum.

Positron emission tomography can be used to identify

abnormalities in cerebral blood flow associated with

specific symptoms. For example, McGuire and

colleagues19 observed that patients who typically

experienced hallucinations had decreased cerebral blood

flow in the cortical areas used to monitor speech, such as

the left middle temporal gyrus and supplementary motor

area. Silbersweig and colleagues20 assessed blood flow in

patients while they were hallucinating. The investigators

observed increased cerebral blood flow primarily in

subcortical and limbic regions, and in the cerebellum.

They speculated that activity in subcortical regions may

generate or moderate hallucinations, whereas the content

(eg, auditory, tactile) may be determined by the specific

neocortical regions that are engaged.

In addition to investigation of symptom correlations,

researchers have used positron emission tomography to

identify dysfunctional neural circuitry used in mental

tasks (eg, remembering faces or word lists, focusing

attention on a target, figure) in patients and healthy

controls. For example, patients with schizophrenia have

significantly lower glucose metabolism in the thalamus

and frontal cortex than controls, on 18F-deoxyglucose

positron emission tomography.21 Glucose metabolism was

measured in 20 patients with schizophrenia who had

never received medication, and showed decreased

thalamic activation during a continuous performance

test.22 Andreasen and colleagues23 found abnormal

regional cerebral blood flow in many frontal subregions,

and in the thalamus and the cerebellum in a study of

practised and novel recall of complex narrative material.Similar abnormalities in episodic memory and semantic

or working memory tasks have been seen.24

Positron emission tomography also enables assessment

of receptor function in vivo. The regulation of dopamine

activity has been well studied, since dopamine

dysregulation is recognised as being inherently involved

in the pathology of schizophrenia.25 A study showed that

striatal dopamine transmission is improved in patients

with schizophrenia who are given an amphetamine

challenge, compared with controls.26

Functional MRI is newer technique that uses

deoxygenated haemoglobin as an endogenous tracer. To

date, only a few patient/control comparisons exist, most

of which show abnormalities in various regions of corticalactivity, such as prefrontal and temporal regions.27 Other

creative and technically advanced techniques are under

development. For example, diffusion tensor imaging

estimates the function of white matter in schizophrenia by

determining directionality of white-matter-tract activity.

Neuroimaging researchers are thus able to quantify

abnormalities in white-matter integrity and activity.28

SEMINAR


Comparison of 12 patients with schizophrenia and 13 healthy

controls in visual attention task shown on positron emissiontomography

D1 D2 5-hydroxytryptamine1A 5-hydroxytryptamine2A -1 -2 H1 M1

Haloperidol 3+ 4+ 0 1+ 2+ 0 0 0

Clozapine 2+ 2+ 1+ 3+ 3+ 3+ 4+ 5+

Risperidone 2+ 4+ 2+ 5+ 3+ 3+ 2+ 0

Olanzapine 3+ 3+ 0 4+ 3+ 0 4+ 5+

Quetiapine 1+ 2+ 0 1+ 4+ 1+ 4+ 3+

H1=histamine receptor. M1=muscarinic receptor.

Receptor affinity of atypical antipsychotic drugs


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Another new approach involves quantification of

functional probes by proton magnetic resonance

spectroscopy. For example, N-acetylaspartate may be

measured through non-invasive magnetic resonance

spectroscopy and provide an estimate of neuronal

function. N-acetylaspartate is specific to neurons and

axons as opposed to glial cells; therefore, neurons can be

selectively identified to find out the integrity of the greymatter, and axons can be assessed to estimate white-

matter integrity. Through selective estimation of N-

acetylaspartate, a possible decrease in neuronal volume in

the anterior hippocampal region in schizophrenia has

been shown.29 Magnetic resonance spectroscopy allows

in-vivo assessment of the metabolic rate of specific

metabolites implicated in schizophrenia, such as

glutamine and glutamate, to identify the presence of a

potential defect in glutamaterigc neurotransmission.

Studies may corroborate postmortem work that

implicates a defect in glutamatergic activity involving

hippocampal N-methyl-D-aspartate receptors in

schizophrenia.30

Imaging technologies continue to reinforce thatmeasurable abnormalities exist in schizophrenia.

Advances in neuroimaging may help researchers to

address the many intriguing questions that remain about

these abnormalities. For example, whether the differences

seen in schizophrenia reflect anatomical or functional

circuits misconnected through abnormal brain

development, neuronal loss, or other regressive changes,

an epiphenomenon of treatment, or pathological sequelae

of long-term illness. A consensus is emerging from

research in first-episode patients who have never received

medication that fundamental differences exist in brain

structure and function which precede treatment and

chronicity effects, although the relative contributions of

other factors need clarification.

Treatment

Medication

Antipsychotic medications have for more than 45 years

substantially lessened the morbidity associated with

schizophrenia. Despite being the mainstay of treatment,

standard antipsychotic medications have been associated

with inadequate efficacy and substantial side-effects.

Traditionally, antipsychotic medications were shown to

be effective because of their ability to antagonise

dopamine receptors. Non-selectivity of this antagonism

led, however, to undesirable effects, such as

extrapyramidal symptoms, which commonly manifest as

muscle rigidity, akathesia (motor restlessness), andtremors or other abnormal muscle movements. In the

past decade, several new agents have become available,

generally termed atypical antipsychotics because of their

more diffuse receptor affinities and lack of extrapyramidal

symptoms. These medications are characterised by a

potentially greater efficacy, especially for negative

symptoms, and a better clinical response in patients

thought to be refractory to treatment.

All antipsychotic medications are superior to placebo in

the treatment of schizophrenia. They lessen positive

symptoms and gradually diminish disturbed thought

processes, but are not curative. Many patients respond

poorly to traditional antipsychotic drugs, and the quality

of response varies from patient to patient.31 Clozapine,risperidone, olanzapine, and quetiapine are among the

first atypical antipsychotic drugs, and may soon be joined

by other agents (eg, ziprasidone and others). In addition

to dopamine D2-receptor blockade, atypical antipsychotic

agents also block serotonin receptors in the frontal cortex

and striatal system, which may help to lessen

extrapyramidal side-effects, and may be related to their

greater efficacy for negative symptoms.

Clozapine was first used in the mid-1970s, but earlyreports of agranulocytosis in 12% of patients delayed its

widespread use. The drug has a broad profile of receptor-

binding affinity (dopamine, serotonin, -adrenergic,

histamine, and muscarinic receptors, table 2). Clozapine

can be beneficial in patients who do not respond to older

antipsychotic medications. One study showed that 30%

of patients refractory to haloperidol responded to

clozapine, compared with only 3% in a trial of

chlorpromazine.32 Another study of treatment-refractory

patients compared controls receiving standard care with

patients receiving clozapine. After discharge, the

clozapine group were less likely to be readmitted to

hospital and had a longer period of successfully living in

the community.33 This finding was supported by a 1-year

study of patients with refractory schizophrenia treated

with clozapine or haloperidol. The clozapine group had

fewer days in hospital during the study period than the

haloperidol group, which led to a lower overall cost of

care per patient each year.34 In terms of symptom

response, clozapine is superior to haloperidol in the

improvement of of positive symptoms, but in a 1-year

outpatient open-label study of clozapine use in patients

with residual positive and negative symptoms, negative

symptoms did not decrease significantly during the

treatment period. An improvement in social and

occupational functioning measures was noted, but did

not improve quality of life.35 Identification is needed of

additional factors that mediate clinical response as newer

agents emerge.

Risperidone represented a new approach to

antipsychotic treatment, referred to as serotonin-

dopamine antagonists. The term reflects risperidones

narrow receptor affinity, since it acts primarily at

dopamine D2 and serotonin 5-hydroxytryptamine2receptors (table). A meta-analysis has shown risperidone

to be potentially more effective than haloperidol.36

Risperidone may be of particular benefit for new-onset

and elderly patients because of its lower side-effect

profile, which leads to greater tolerance and likelihood for

compliance. One study of risperidone in elderly patients

with psychosis showed improvement in cognition over the

treatment period.37 There is emerging evidence that

risperidone may also be of benefit for treatment-resistant

patients.38

Olanzapine became available in the past 2 years. It has

wide receptor affinity, with the exception of serotonin

5-hydroxytryptamine1A and -2 adrenergic receptors

(table). Some evidence suggests that olanzapine is more

effective than haloperidol in the lessening of negative

symptoms.39 Furthermore, olanzapine does not seem to

induce extrapyramidal symptoms when used in

therapeutic doses. Newer agents with various broad

receptor profiles continue to be developed, such as

quetiapine, which has a weak affinity for D2 receptors. A

meta-analysis of the three studies of quetiapine concluded

that it was effective for positive and negative symptoms,

without evidence of extrapyramidal symptoms.40 Futurework will continue to define the precise combination of



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receptor action that confers the greatest therapeutic

benefit with the least adverse effects. Dopamine and

serotonin antagonism are of therapeutic benefit, but the

contributions of other receptor actions are not yet clear.

Although newer agents may bring greater efficacy and

tolerability, the choice of antipsychotic medications

should be individualised for each patient. The newer

agents, as do the standard agents, affect receptors almost

immediately, yet all take at least several weeks before an

optimum response is seen. Patience and compliance with

treatment are therefore important if response is delayed

to pharmacological management of schizophrenia.

Controlled studies do not support use of specific agents

for specific subtypes of schizophrenia, nor is there any

benefit from prescription of more than one antipsychotic

at a time. Drug selection should rely on knowledge about

possible side-effects, the patients previous treatment

response, and, if appropriate, the patients family history

of drug response.

Psychosocial interventions

In the past few years interest has been renewed in the

importance of social support and a growing recognition of

the need to better address the psychosocial needs of each

individual. This change has led to research efforts geared

toward the development of treatment models and

assessment tools to measure progress in social

rehabilitation. In 1996, the Patient Outcomes Research

Team for Schizophrenia (PORT) study41 assessed the

impact of different therapeutic techniques on functional

outcome and use of services. This group performed an

exhaustive analysis of the outcome literature in

schizophrenia to determine key recommendations for all

features of treatment. In addition to highlighting the

importance of continuing medication management, the

group addressed the importance of psychological support,

family interventions, vocational rehabilitation, and

community support. They emphasised that support,

education, crisis intervention, and training in problem-

solving are beneficial for patients, families, and non-

family carers, especially in the initial stages of

schizophrenia. The importance of vocational training wasalso emphasised, as well as the use of assertive case

management and community treatment programmes for

patients who are high service-users or more severely

impaired.

Psychological interventions may have a substantial

economic impact by decreasing the degree of service use

for acute-care needs. For example, a controlled

prospective study of the use of cognitive therapy in acute

non-affective psychosis showed a more striking decline in

positive symptoms in the cognitive-therapy group initially

and a substantially decreased symptom burden after

9 months of follow-up. This study also showed a shorter

total time to recovery to baseline functioning after an

acute episode.42 Increases in economic constraints willdemand further investigations such as this to keep illness

management to an optimum in this population.

Psychosocial support and community interventions are

fundamental to access to medical care and compliance

with antipsychotic medications. Given the dramatic

impairments associated with schizophrenia, the necessity

of maximum psychosocial support cannot be emphasised

enough. Differences in health-care delivery across nations

make provision of optimum care challenging. Much

research is however still needed to change the emotional

and social burdens incurred by schizophrenia.

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and selected findings. Schizophr Res 1997; 27: 24959.

39 Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo

and haloperidol.Neuropsychopharmacology 1996;14:

11123.40 Meats P. Quetiapine (Seroquel): an effective and well-tolerated

atypical antipsychotic. Intl J Psychiatr Clin Pract1997; 1: 23139.

41 Lehman, AF, Steinwachs DM, Dixon LB, et al. Translating research

into practice: the Schizophrenia Patient Outcomes Research Team

(PORT) treatment recommendations. Schizophr Bull1998; 24: 120.

42 Drury V, Birchwood M, Cochrane R., Macmillian F. Cognitive

therapy and recovery from acute psychosis: a controlled trial I impact

on psychotic symptoms and II impact on recovery time. Br J Psychiatry

1996, 169: 593607.


Further reading

Diagnostic Issues in SchizophreniaBuchanan RW, Gold JM. Negative symptoms: diagnosis, treatment and

prognosis. Intl Clin Psychopharmacol1996; 11 (suppl 2): 311.

Earnst KS, Kring AM. Construct validity of negative symptoms: an

empirical and conceptual review. Clin Psychol Rev1997; 17: 11432.

Falkai P. Differential diagnosis in acute psychotic episode. Intl ClinPsychopharmacol1996; 11 (suppl 2): 1317.

Flaum M, Schultz SK. The core symptoms of schizophrenia. Ann Med

1996; 28: 52531.

Malla AK. Negative symptoms and affective disturbance in schizophrenia

and related disorders. Can J Psychiatry1995; 40 (suppl 2): S5559.

Genetic factors in schizophreniaMowry BL, Nancarrow DJ, Levinson DF. The molecular genetics of

schizophrenia: an update. Aus N Z J Psychiatry1997; 5: 70413.

ODonovan MC, Owen MJ. The molecular genetics of schizophrenia. Ann

Med1996; 6: 54146.

Portin P, Alanen YO. A critical review of genetic studies of schizophrenia II

molecular genetic studies. Acta Pschiatr Scan1997; 2: 7380.

Neural substrates of schizophreniaArnold SE, Trojanowski JQ. Recent advances in defining the

neuropathology of schizophrenia. Acta Neuropathol1996; 3: 21731.

Frangou S, Murray RM. Imaging as a tool in exploring theneurodevelopment and genetics of schizophrenia. Br Med Bull1996;

3: 58796.

Kinderman SS, Karimi A, Symonds L, Brown GG, Jeste DV. Review of

functional magnetic resonance imaging in schizophrenia. Schizophr

Res1997; 27: 14356.

Shenton ME, Wible CG, McCarley RW. A review of magnetic resonance

imaging studies of brain anomalies in schizophrenia In: Krishnan KRR,

Doraiswamy PM, eds. Brain imaging in clinical psychiatry. New York:

Marcel Dekker, 1997.

Stefan MD, Murray RM. Schizophrenia: developmental disturbance of

brain and mind? Acta Paediatr1997; 422 (suppl): 11216.

Treatment issues

Fleishacker WW, Hummer M. Drug treatment of schizophrenia in the

1990s: achievements and future possibilities in optimising outcomes.

Drugs1997; 6: 91529.

Hogarty GE, Kornblith SJ, Greenwald D, et al. Three-year trials of personal

therapy among schizophrenic patients living with or independent of

family, I and II. Am J Psychiatry1997; 11: 150424.

Kopala LC. Clinical experience in developing treatment regimens with the

novel antipsychotic risperidone. Intl Clin Psychopharmacol1997; 4

(suppl 11): S118.

Peuskens J. Proper psychosocial rehabilitation for stabilised patients with

schizophrenia: the role of new therapies. Eur Neuropsychopharmacol

1996; 2 (suppl): S712.

andreasen, n. - schizophrenia

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