- Email: [email protected]
Schizophrenia
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Seminar
Schizophrenia Susan K Schultz, Nancy C Andreasen Schizophrenia is among the most severe and debilitating of psychiatric disorders. Diagnosis is currently by criterionbased 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. Schizophrenia is a devastating illness. It is characterised by 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 5·4% 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 £2·6 billion was estimated.1 In vulnerable groups, such as the homeless, the cost of this illness may be even higher. In a report on hospitaladmission costs among the homeless in New York City, USA, 80·6% 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 Lancet 1999; 353: 1425–30 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])
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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 steroidinduced 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 healtheconomics 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 identified and a direct measure of the pathology has been found, 1425
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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 during adolescence, 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.
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 development of 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 tenfold 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 2·0 for an association between exposure to obstetric complicatons and development of schizophrenia. Verdoux and colleagues9 used data from 11 research groups involving 1426
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 follows simple 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 regions—D6S274 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 chromosomes 3, 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 in association 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 the expression 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 Alzheimer’s 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 of regions are affected rather than gross brain abnormalities.
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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 cortical activity, 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
Comparison of 12 patients with schizophrenia and 13 healthy controls in visual attention task shown on positron emission tomography
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 higher cortical 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 positron emission 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
Haloperidol Clozapine Risperidone Olanzapine Quetiapine
D1
D2
5-hydroxytryptamine1A
5-hydroxytryptamine2A
␣-1
␣-2
H1
M1
3+ 2+ 2+ 3+ 1+
4+ 2+ 4+ 3+ 2+
0 1+ 2+ 0 0
1+ 3+ 5+ 4+ 1+
2+ 3+ 3+ 3+ 4+
0 3+ 3+ 0 1+
0 4+ 2+ 4+ 4+
0 5+ 0 5+ 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 grey matter, and axons can be assessed to estimate whitematter integrity. Through selective estimation of Nacetylaspartate, 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 that measurable 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), and tremors 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 1428
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 early reports of agranulocytosis in 1–2% of patients delayed its widespread use. The drug has a broad profile of receptorbinding affinity (dopamine, serotonin, α-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 serotonindopamine antagonists. The term reflects risperidone’s narrow receptor affinity, since it acts primarily at dopamine D2 and serotonin 5-hydroxytryptamine2 receptors (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 α-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 Future work 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 patient’s previous treatment response, and, if appropriate, the patient’s 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
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Knapp M. Costs of schizophrenia. Br J Psychiatry 1997; 171: 509–18. Salit SA, Kuhn EM, Hartz AJ, Vu JM, Mossa AL. Hospitalization costs associated with homelessness in New York City. N Engl J Med 1998; 338: 1734–40. World Health Organization. International classification of diseases, 10th edn. Geneva: WHO, 1994. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn (DSM-IV). Washington, DC: American Psychiatric Press, 1994. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia. Am J Psychiatry 1996; 153: 321–30. Hull JW, Smith TE, Anthony DT, et al. Patterns of symptom change: a longitudinal analysis. Schizophr Res 1997; 24: 17–18. McGuffin P, Owen MJ, Farmer AE. Genetic basis of schizophrenia. Lancet 1996; 346: 678–82. Geddes JR, Lawrie SM. Obstetric complications and schizophrenia: a meta-analysis. Br J Psychiatry 1995; 167: 786–93. Verdoux H, Geddes JR, Takei N, et al. Obstetric complications and age at onset in schizophrenia: an international collaborative metaanalysis of individual patient data. Am J Psychiatry 1997; 154: 1220–27. Moldin SO, Gottesman II. At issue: genes, experience and chance in schizophrenia: positioning for the 21st century. Schizophr Bull 1997; 23: 547–61. Turecki G, Rouleau GA, Joober R, Mari J, Morgan K. Schizophrenia and chromosome 6. Am J Med Genet 1997; 74: 195–98. Levinson DF, Mahtani MM, Nancarrow DJ. Genome scan of schizophrenia. Am J Psychiatry 1998; 155: 741–50. Freedman R. Basic and clinical approaches to the genetics of deficits in schizophrenia. Biol Psychiatry 1998; 43 (suppl 8S): 3S. Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55: 225–32. Ward K E, Friedman L, Wise A, Schulz SC. Meta-analysis of brain and cranial size in schizophrenia. Schizophr Res 1996; 22: 197–223.
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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 problemsolving are beneficial for patients, families, and nonfamily carers, especially in the initial stages of schizophrenia. The importance of vocational training was also 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 will demand 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. 16 Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998, 172: 110–20. 17 Lim KO, Tew W, Kushner M, et al. Cortical gray matter volume deficit in patients with first-episode schizophrenia. Am J Psychiatry 1996; 153: 1548–53. 18 Schlaepfer TE, Harris GJ, Tien AY, et al. Diseased regional cortical gray matter volume in schiozphrenia. Am J Psychiatry 1994; 151: 842. 19 McGuire PK, Silbersweig DA, Wright I, et al. The neural correlates of inner speech and auditory verbal imagery in schizophrenia: relationship to auditory verbal hallucinations. Br J Psychiatry 1996; 169: 148–59. 20 Silbersweig DA, Stern E, Frith C, et al. A functional neuroanatomy of hallucinations in schizophrenia. Nature 1995; 378: 176–79. 21 Buchsbaum MS, Haier RJ, Potkin SG, et al. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry 1992; 49: 935–42. 22 Buchsbaum MS, Someya T, Teng CY, et al. PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 1996; 153: 191–99. 23 Andreasen NC. Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology. Science 1996; 275: 1586–93. 24 Gur RC, Gur RE. Hypofrontality in schizophrenia: RIP. Lancet 1995; 345: 1383–84. 25 Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RS, Grasby PM. Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature. 1995; 378: 180–82. 26 Abi-Dargham A, Gil R, Krystal J, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–67. 27 Yurgelun-Todd DA, Waternaux CM, Cohen BM, et al. Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 1996; 153: 200–05. 28 Lim KO, Hedehus M, de Crespigny A, Menon V, Moseley M.
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31 32 33
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Diffusion tensor imaging of white matter tracts in schizophrenia. Biol Psychiatry 1998; 43 (suppl 8S): 11S. Deicken RF, Pegues M, Amend D, Bloomer C, Weiner M. Hippocampal neuronal loss in schizophrenia as measured by proton MRSI. Biol Psychiatry, 1998; 43 (supple 8S): 25S. Williamson R., Bartha R, Drost D. 1H-MRS Imaging of glutamate and glutamine in schizophrenic patients. Biol Psychiatry. 1998; 43 (suppl 8S): 7S. Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 1998; 12: 21–36. Kane J, Honingfeld G, Singer J, et al. Clozapine for treatmentresistant schizophrenia. Arch Gen Psychiatry 1988; 45: 789–96. Essock SM, Hargreaves WA, Covell NH, Goethe J: Antipsychotics in research and clinical settings. Psychopharmacol Bull 1996; 32: 683–97. Rosenheck R, Cramer J, Xu W, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809–15. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter W. Positive
Further reading
Diagnostic Issues in Schizophrenia Buchanan RW, Gold JM. Negative symptoms: diagnosis, treatment and prognosis. Intl Clin Psychopharmacol 1996; 11 (suppl 2): 3–11. Earnst KS, Kring AM. Construct validity of negative symptoms: an empirical and conceptual review. Clin Psychol Rev 1997; 17: 114–32. Falkai P. Differential diagnosis in acute psychotic episode. Intl Clin Psychopharmacol 1996; 11 (suppl 2): 13–17. Flaum M, Schultz SK. The core symptoms of schizophrenia. Ann Med 1996; 28: 525–31. Malla AK. Negative symptoms and affective disturbance in schizophrenia and related disorders. Can J Psychiatry 1995; 40 (suppl 2): S55–59.
Genetic factors in schizophrenia Mowry BL, Nancarrow DJ, Levinson DF. The molecular genetics of schizophrenia: an update. Aus N Z J Psychiatry 1997; 5: 704–13. O’Donovan MC, Owen MJ. The molecular genetics of schizophrenia. Ann Med 1996; 6: 541–46. Portin P, Alanen YO. A critical review of genetic studies of schizophrenia II molecular genetic studies. Acta Pschiatr Scan 1997; 2: 73–80.
Neural substrates of schizophrenia Arnold SE, Trojanowski JQ. Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol 1996; 3: 217–31. Frangou S, Murray RM. Imaging as a tool in exploring the neurodevelopment and genetics of schizophrenia. Br Med Bull 1996; 3: 587–96.
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and negative symptom response to clozapine in schizophrenia. 1998; 155: 751–60. Davis JM, Janicak PG, Risperidone: a new, novel (and better?) antipsychotic. Psychiatr Ann 1996; 26: 78–87. Jeste DV, Eastham JH, Lacro JP, et al, Management of late-life psychosis. J Clin Psychiatry 1996; 57: 39–45. Schooler NR. New antipsychotic medications: strategies for evaluation and selected findings. Schizophr Res 1997; 27: 249–59. Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol. Neuropsychopharmacology 1996; 14: 111–23. Meats P. Quetiapine (Seroquel): an effective and well-tolerated atypical antipsychotic. Intl J Psychiatr Clin Pract 1997; 1: 231–39. Lehman, AF, Steinwachs DM, Dixon LB, et al. Translating research into practice: the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations. Schizophr Bull 1998; 24: 1–20. 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: 593–607.
Kinderman SS, Karimi A, Symonds L, Brown GG, Jeste DV. Review of functional magnetic resonance imaging in schizophrenia. Schizophr Res 1997; 27: 143–56. 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 Paediatr 1997; 422 (suppl): 112–16.
Treatment issues Fleishacker WW, Hummer M. Drug treatment of schizophrenia in the 1990s: achievements and future possibilities in optimising outcomes. Drugs 1997; 6: 915–29. 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 Psychiatry 1997; 11: 1504–24. Kopala LC. Clinical experience in developing treatment regimens with the novel antipsychotic risperidone. Intl Clin Psychopharmacol 1997; 4 (suppl 11): S11–8. Peuskens J. Proper psychosocial rehabilitation for stabilised patients with schizophrenia: the role of new therapies. Eur Neuropsychopharmacol 1996; 2 (suppl): S7–12.
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Seminar
Schizophrenia Susan K Schultz, Nancy C Andreasen Schizophrenia is among the most severe and debilitating of psychiatric disorders. Diagnosis is currently by criterionbased 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. Schizophrenia is a devastating illness. It is characterised by 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 5·4% 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 £2·6 billion was estimated.1 In vulnerable groups, such as the homeless, the cost of this illness may be even higher. In a report on hospitaladmission costs among the homeless in New York City, USA, 80·6% 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 Lancet 1999; 353: 1425–30 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])
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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 steroidinduced 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 healtheconomics 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 identified and a direct measure of the pathology has been found, 1425
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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 during adolescence, 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.
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 development of 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 tenfold 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 2·0 for an association between exposure to obstetric complicatons and development of schizophrenia. Verdoux and colleagues9 used data from 11 research groups involving 1426
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 follows simple 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 regions—D6S274 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 chromosomes 3, 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 in association 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 the expression 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 Alzheimer’s 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 of regions are affected rather than gross brain abnormalities.
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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 cortical activity, 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
Comparison of 12 patients with schizophrenia and 13 healthy controls in visual attention task shown on positron emission tomography
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 higher cortical 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 positron emission 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
Haloperidol Clozapine Risperidone Olanzapine Quetiapine
D1
D2
5-hydroxytryptamine1A
5-hydroxytryptamine2A
␣-1
␣-2
H1
M1
3+ 2+ 2+ 3+ 1+
4+ 2+ 4+ 3+ 2+
0 1+ 2+ 0 0
1+ 3+ 5+ 4+ 1+
2+ 3+ 3+ 3+ 4+
0 3+ 3+ 0 1+
0 4+ 2+ 4+ 4+
0 5+ 0 5+ 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 grey matter, and axons can be assessed to estimate whitematter integrity. Through selective estimation of Nacetylaspartate, 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 that measurable 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), and tremors 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 1428
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 early reports of agranulocytosis in 1–2% of patients delayed its widespread use. The drug has a broad profile of receptorbinding affinity (dopamine, serotonin, α-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 serotonindopamine antagonists. The term reflects risperidone’s narrow receptor affinity, since it acts primarily at dopamine D2 and serotonin 5-hydroxytryptamine2 receptors (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 α-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 Future work 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 patient’s previous treatment response, and, if appropriate, the patient’s 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
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Knapp M. Costs of schizophrenia. Br J Psychiatry 1997; 171: 509–18. Salit SA, Kuhn EM, Hartz AJ, Vu JM, Mossa AL. Hospitalization costs associated with homelessness in New York City. N Engl J Med 1998; 338: 1734–40. World Health Organization. International classification of diseases, 10th edn. Geneva: WHO, 1994. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn (DSM-IV). Washington, DC: American Psychiatric Press, 1994. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia. Am J Psychiatry 1996; 153: 321–30. Hull JW, Smith TE, Anthony DT, et al. Patterns of symptom change: a longitudinal analysis. Schizophr Res 1997; 24: 17–18. McGuffin P, Owen MJ, Farmer AE. Genetic basis of schizophrenia. Lancet 1996; 346: 678–82. Geddes JR, Lawrie SM. Obstetric complications and schizophrenia: a meta-analysis. Br J Psychiatry 1995; 167: 786–93. Verdoux H, Geddes JR, Takei N, et al. Obstetric complications and age at onset in schizophrenia: an international collaborative metaanalysis of individual patient data. Am J Psychiatry 1997; 154: 1220–27. Moldin SO, Gottesman II. At issue: genes, experience and chance in schizophrenia: positioning for the 21st century. Schizophr Bull 1997; 23: 547–61. Turecki G, Rouleau GA, Joober R, Mari J, Morgan K. Schizophrenia and chromosome 6. Am J Med Genet 1997; 74: 195–98. Levinson DF, Mahtani MM, Nancarrow DJ. Genome scan of schizophrenia. Am J Psychiatry 1998; 155: 741–50. Freedman R. Basic and clinical approaches to the genetics of deficits in schizophrenia. Biol Psychiatry 1998; 43 (suppl 8S): 3S. Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55: 225–32. Ward K E, Friedman L, Wise A, Schulz SC. Meta-analysis of brain and cranial size in schizophrenia. Schizophr Res 1996; 22: 197–223.
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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 problemsolving are beneficial for patients, families, and nonfamily carers, especially in the initial stages of schizophrenia. The importance of vocational training was also 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 will demand 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. 16 Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998, 172: 110–20. 17 Lim KO, Tew W, Kushner M, et al. Cortical gray matter volume deficit in patients with first-episode schizophrenia. Am J Psychiatry 1996; 153: 1548–53. 18 Schlaepfer TE, Harris GJ, Tien AY, et al. Diseased regional cortical gray matter volume in schiozphrenia. Am J Psychiatry 1994; 151: 842. 19 McGuire PK, Silbersweig DA, Wright I, et al. The neural correlates of inner speech and auditory verbal imagery in schizophrenia: relationship to auditory verbal hallucinations. Br J Psychiatry 1996; 169: 148–59. 20 Silbersweig DA, Stern E, Frith C, et al. A functional neuroanatomy of hallucinations in schizophrenia. Nature 1995; 378: 176–79. 21 Buchsbaum MS, Haier RJ, Potkin SG, et al. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry 1992; 49: 935–42. 22 Buchsbaum MS, Someya T, Teng CY, et al. PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 1996; 153: 191–99. 23 Andreasen NC. Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology. Science 1996; 275: 1586–93. 24 Gur RC, Gur RE. Hypofrontality in schizophrenia: RIP. Lancet 1995; 345: 1383–84. 25 Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RS, Grasby PM. Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature. 1995; 378: 180–82. 26 Abi-Dargham A, Gil R, Krystal J, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–67. 27 Yurgelun-Todd DA, Waternaux CM, Cohen BM, et al. Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 1996; 153: 200–05. 28 Lim KO, Hedehus M, de Crespigny A, Menon V, Moseley M.
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31 32 33
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Diffusion tensor imaging of white matter tracts in schizophrenia. Biol Psychiatry 1998; 43 (suppl 8S): 11S. Deicken RF, Pegues M, Amend D, Bloomer C, Weiner M. Hippocampal neuronal loss in schizophrenia as measured by proton MRSI. Biol Psychiatry, 1998; 43 (supple 8S): 25S. Williamson R., Bartha R, Drost D. 1H-MRS Imaging of glutamate and glutamine in schizophrenic patients. Biol Psychiatry. 1998; 43 (suppl 8S): 7S. Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 1998; 12: 21–36. Kane J, Honingfeld G, Singer J, et al. Clozapine for treatmentresistant schizophrenia. Arch Gen Psychiatry 1988; 45: 789–96. Essock SM, Hargreaves WA, Covell NH, Goethe J: Antipsychotics in research and clinical settings. Psychopharmacol Bull 1996; 32: 683–97. Rosenheck R, Cramer J, Xu W, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809–15. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter W. Positive
Further reading
Diagnostic Issues in Schizophrenia Buchanan RW, Gold JM. Negative symptoms: diagnosis, treatment and prognosis. Intl Clin Psychopharmacol 1996; 11 (suppl 2): 3–11. Earnst KS, Kring AM. Construct validity of negative symptoms: an empirical and conceptual review. Clin Psychol Rev 1997; 17: 114–32. Falkai P. Differential diagnosis in acute psychotic episode. Intl Clin Psychopharmacol 1996; 11 (suppl 2): 13–17. Flaum M, Schultz SK. The core symptoms of schizophrenia. Ann Med 1996; 28: 525–31. Malla AK. Negative symptoms and affective disturbance in schizophrenia and related disorders. Can J Psychiatry 1995; 40 (suppl 2): S55–59.
Genetic factors in schizophrenia Mowry BL, Nancarrow DJ, Levinson DF. The molecular genetics of schizophrenia: an update. Aus N Z J Psychiatry 1997; 5: 704–13. O’Donovan MC, Owen MJ. The molecular genetics of schizophrenia. Ann Med 1996; 6: 541–46. Portin P, Alanen YO. A critical review of genetic studies of schizophrenia II molecular genetic studies. Acta Pschiatr Scan 1997; 2: 73–80.
Neural substrates of schizophrenia Arnold SE, Trojanowski JQ. Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol 1996; 3: 217–31. Frangou S, Murray RM. Imaging as a tool in exploring the neurodevelopment and genetics of schizophrenia. Br Med Bull 1996; 3: 587–96.
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and negative symptom response to clozapine in schizophrenia. 1998; 155: 751–60. Davis JM, Janicak PG, Risperidone: a new, novel (and better?) antipsychotic. Psychiatr Ann 1996; 26: 78–87. Jeste DV, Eastham JH, Lacro JP, et al, Management of late-life psychosis. J Clin Psychiatry 1996; 57: 39–45. Schooler NR. New antipsychotic medications: strategies for evaluation and selected findings. Schizophr Res 1997; 27: 249–59. Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol. Neuropsychopharmacology 1996; 14: 111–23. Meats P. Quetiapine (Seroquel): an effective and well-tolerated atypical antipsychotic. Intl J Psychiatr Clin Pract 1997; 1: 231–39. Lehman, AF, Steinwachs DM, Dixon LB, et al. Translating research into practice: the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations. Schizophr Bull 1998; 24: 1–20. 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: 593–607.
Kinderman SS, Karimi A, Symonds L, Brown GG, Jeste DV. Review of functional magnetic resonance imaging in schizophrenia. Schizophr Res 1997; 27: 143–56. 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 Paediatr 1997; 422 (suppl): 112–16.
Treatment issues Fleishacker WW, Hummer M. Drug treatment of schizophrenia in the 1990s: achievements and future possibilities in optimising outcomes. Drugs 1997; 6: 915–29. 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 Psychiatry 1997; 11: 1504–24. Kopala LC. Clinical experience in developing treatment regimens with the novel antipsychotic risperidone. Intl Clin Psychopharmacol 1997; 4 (suppl 11): S11–8. Peuskens J. Proper psychosocial rehabilitation for stabilised patients with schizophrenia: the role of new therapies. Eur Neuropsychopharmacol 1996; 2 (suppl): S7–12.
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