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Challenges in schizophrenia diagnosis

From the 1980s, the consensus that schizophrenia is a ‘neurodevelopmental disorder’ largely regarded as attributable to genetic factors became well established. Nevertheless, major challenges in diagnosis persist, not least the fact that the diagnosis of schizophrenia remains entirely clinical, requiring the careful elucidation of symptoms through meticulous history taking, with reference to current diagnostic criteria.

In May 2013, the American Psychiatric Association published its latest diagnostic criteria, DSM-V, in an effort to bring clinical thinking into line with developments in cognitive neuroscience, brain imaging, epidemiology and genetics since its last iteration 14 years ago. The new classificatory system represents an effort to move away from discrete illness categories towards a broadening of symptom domains along dimensions, in an effort to represent some recognition that clear boundaries between disease entities may not be as robust as previously imagined.

It also seeks to recognise that clinical disease states may shift and change over time in a much more fluid manner than DSM-IV had allowed. It is hoped that this will allow for a greater understanding of pathophysiological processes, an appreciation of complex comorbidities and the creation of more comprehensive therapeutic agendas, with the ultimate aim of leading to better outcomes for patients. In Europe, we tend to rely upon the World Health Organisation International Statistical Classification of Diseases and Related Health Problems (ICD-10) classificatory system. However DSM-5 has been constructed in anticipation of the forthcoming ICD-11, with the view to achieving greater harmonisation. Consequently, both systems may be used more or less interchangeably.

Symptoms

Schizophrenia and related disorders are defined by abnormalities in one or more of the following five domains: delusions; hallucinations; disorganised thinking (speech); grossly disorganised or abnormal motor behaviour (including catatonia); and negative symptoms. Negative symptoms account for a substantial portion of the morbidity associated with schizophrenia but because they do not come to attention in the prominent way that positive symptoms do, they may be overlooked or mistaken for medication side-effects or depression. Negative symptoms that are particularly prominent include diminished emotional expression and loss of willpower or drive.

There has been much emphasis on the primacy of the so-called positive symptoms such as hallucinations or delusions, which are often recognised as the hallmark of ‘madness’ and are overly represented in Hollywood depictions of mental illness. However, it is those negative symptoms that lead to the greatest functional impairment and impact on patients’ quality of life. It is now clear that schizophrenia is much more than a ‘psychotic disorder’, with an increasing focus on cognition, with evidence that cognitive impairment generally precedes the onset of psychosis by up to five years before presentation. Ironically, this cognitive impairment may have been recognised by the earliest writers on the topic of schizophrenia when Kraeplin referred to the disorder as “dementia praecox”, before Blueler later coined the term schizophrenia.

Schizophrenia confers considerable morbidity and is associated with significant mortality, with a reduced life expectancy of on average 20 years compared to the non-affected population. While in general, life expectancies have been increasing, epidemiology shows a widening gap between those with schizophrenia and those without.

This increased mortality is associated with an increased rate of suicide. Another contributing factor to early mortality relates to cardiovascular disease and metabolic syndrome.

Risk factors

Concerning identifiable risk factors, researchers have identified some contribution from perinatal complications, paternal age, gender (male>female) degree of urbanicity, migration status, social adversity and drug abuse. Some of these could be addressed through social policy, whereas other risk factors are less easy to modify.

The effort to understand the origin of psychotic symptoms remains engaged in an attempt to bridge a computational model of neural networks and intracellular communications problems, underpinned by the ‘holy grail’ of identifying some gene or receptor structural flaw which could be treated by a drug.

The dominant paradigm continues to rest on drug treatment strategies that modify dopamine, although other neurotransmitter systems have been the subject of extensive research, such as NDMA (a subtype of glutamate) and the GABA system; these have yet to provide alternative treatment strategies.

It has long been recognised that schizophrenia is highly heritable, with concordance rates of almost 50 per cent in monozygotic twins. Schizophrenia is regarded as arising from a complicated interaction between genetic risk factors and environmental influences. There are an increasing number of genes identified as conferring some small degree of risk. It is likely therefore that we all carry some risk-related genes.

It is reported that many genes implicated as risk factors for schizophrenia are also involved in foetal development. Research has attempted to identify what environmental influences may impact on neurodevelopment, focusing on the second trimester and, for example, possible maternal exposure to viral infection, such as influenza.

While attempts to identify some fundamental cause that could lead to an effective prevention or drug treatment strategy continue, there remains the immediate challenge of providing treatments for active symptoms and problem behaviours. A better understanding of the relationship between active symptoms, behaviours and the underlying pathophysiology of the disorder should lead to more effective treatments.

Functional neuroimaging studies are leading to an increasing understanding of relationships between anatomical regions of interest, such as functional impairment in neural network interconnectedness with neuro-psychological measures of processing, memory and information salience. There may be an emerging confluence between molecular genetic research and higher-level functional research. For instance, environmental risk factors, such as being born and brought up in a city and migration status, are recognised as contributing ‘social stress’, which may be mediated through genetic risk factors, leading to an increased risk of schizophrenia. It has been argued that this stress is mediated through a cingulate-amygdala circuit, which in turn may be modified by genes that express receptors for serotonin.

Prevention?

While not everyone who is subject to the range of social stresses that have been identified as contributing some degree of risk for schizophrenia will go on to develop the disorder, there has been an effort to identify what collection of risk factors could define a group at particularly high risk. Such a group might then benefit from an early intervention.

Most patients who go on to develop schizophrenia first go through a prodrome where social and functional impairments arise before the onset of psychotic symptoms and where it is believed that much of the decline associated with schizophrenia will have become established. Intervening with treatment as soon as possible following diagnosis of psychotic symptoms has yielded only modest improvement in outcome.

However, this has spurred efforts to intervene before the onset of frank psychosis. Recognising this prodrome has led to the design of operational criteria for people deemed to be at high risk. This led to the characterisation of what has been called a sub-threshold psychotic syndrome or attenuated psychosis syndrome.

Flynn et al report in BMC Psychiatry (2012) that 23 per cent of 171 young male offenders met criteria for ultra high-risk when interviewed using the Comprehensive Assessment of at-risk Mental States. That rate was higher than reported in community samples and was associated with impaired function, suggesting that it may be part of a developing disorder. Eighty-five per cent of the sample admitted substance use problems (cannabis, mephedrone, alcohol, ecstasy, amphetamines, cocaine, benzodiazepines and heroin).  This study also demonstrated a correlation between the number of substance use problems and ultra high-risk status, ie, the more intoxicants a person used, the greater the probability that they would meet criteria.

Interestingly, a Finnish study (N=18,478) (Niemi-Pynttari et al, J Clin Psychiatry 2013) followed all patients since the first inpatient hospital admission with a diagnosis of substance-induced psychosis between January 1987 and December 2003.

They reported that the eight-year cumulative risk to receive a diagnosis of schizophrenia spectrum disorder was 46 per cent for people who were diagnosed with cannabis-induced psychosis and 30 per cent for those with an amphetamine-induced psychosis.

Although alcohol-induced psychosis was the most common type of substance-induced psychosis, the eight-year cumulative risk of subsequent schizophrenia spectrum diagnosis was only 5 per cent.  Reverting to the ultra high-risk field, Simon et al in Psychiatry Research (2013) report emerging evidence that the transition rates from an initial clinical high-risk status to psychosis have been decreasing.

They argue therefore that a cautious approach should be adopted in order to reduce the risk of stigma and inappropriate treatment being recommended to adolescents identified as at high risk. However, it should be recognised that even the exercise of conducting an assessment may have a therapeutic effect, insofar as the assessor is quite likely to advise an adolescent deemed to be at high risk not to smoke cannabis. The question arises as to what extent such advice may be adopted and if it has been adopted, could that itself translate into a decreasing conversion rate from high-risk status into schizophrenia?

The identification as early as possible of those at greatest risk of developing schizophrenia in the hope that early intervention will lead to altering the trajectory of future illness, perhaps even preventing it, has become public policy. To that end, the College of Psychiatry of Ireland is developing an early intervention strategy as part of one of a series of national clinical programmes.

Another objective is the challenge of providing substance misuse and dual diagnosis services. Perhaps these are linked, at least in those susceptible adolescents who use intoxicants, especially cannabis.

Points for consideration:

  1. Schizophrenia is a severe and potentially devastating disorder, which has a marked negative effect on life expectancy, shortening lives by on average 20 years.
  2. Prevalence is estimated at 1 per cent of the population. The prevalence in prison populations is disproportionately high — remand, 7 per cent vs sentenced, 4 per cent, indicative of the adverse behavioural and social impact of the disorder and probably reflective of stigma and problems with service access.
  3. A higher frequency of relapse is associated with poorer prognosis. Relapse often follows non-adherence to treatment and/or substance misuse. Relapse may occur spontaneously.
  4. Mortality is associated with increased rates of suicide and cardiovascular death.
  5. Identification of comorbid disorders such as depression, substance misuse and metabolic syndrome, leading to more appropriate treatment, in addition to smoking cessation strategies, could help offset some of that risk.
  6. Greater antipsychotic treatment adherence leads to better outcomes and reduced mortality, however long-term benzodiazepine use is associated with increased mortality (Tihonen J et al (2015) AJP).
  7. Drug-induced (especially cannabis) psychosis is a risk factor for schizophrenia requiring evaluation and should not be an exclusion criterion.
  8. While positive symptoms respond to medication, negative symptoms do not and are grounded in cognitive impairment. For that reason, many patients will need ongoing psychosocial support and continuing multidisciplinary treatment, care and follow-up. 
  9. A multi-agency treatment plan with service user and carer engagement, with regular care planning meetings, is the gold standard.
  10. For current diagnostic criteria, refer to DSM-5 or ICD-10.
  11. For current treatment guidelines, refer to NICE (www.nice.org.uk/guidance/cg82).

Current treatment options

A range of pharmacological treatments have been developed, which show varying degrees of efficacy in the treatment of hallucinations and delusions. Unfortunately, there are as yet no pharmacological treatments that show evidence of improvement in those neurocognitive negative symptoms. Psychological treatment strategies are being developed, such as cognitive remediation therapy, in an attempt to address cognitive impairment and related behavioural problems.

There is also increasing recognition of the need to consider carefully what treatment strategies to adopt in addressing hallucinations and delusions, while taking care not to exacerbate cognitive impairments through, for instance, the anticholinergic side-effects of some drugs. Efforts are ongoing in the field of pharmacogenomics, which it is hoped will soon translate from the laboratory to the clinic and speed-up the selection of a tailored treatment strategy for each patient.  As matters stand, clinicians can rely on international guidelines such as NICE (www.nice.org.uk/guidance/cg82) when offering treatment advice.

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