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Schizophrenia: Causes, treatments and outcomes

By Prof Brendan Kelly, Professor of Psychiatry at Trinity College Dublin - 20th Aug 2018

Schizophrenia is a common mental illness that has significant effects, not only on patients and families, but also on the mental health system in general. In addition, schizophrenia is often the subject of much misunderstanding, despite a welcome increase in public discussion of mental health issues in the media in recent years.

Schizophrenia tends to first emerge in the late teens or early 20s and is more common in men than women. Symptoms often commence with very subtle changes in childhood thinking and behaviour, but these changes are so vague and non-specific that they are only recognisable when looking back many years later or in research studies. The vast majority of children with such subtle abnormalities do not develop any psychological or psychiatric problems, nor is there any known intervention indicated for them at that point. So, while these abnormalities cannot be used to diagnose schizophrenia or intervene at that very early stage, they still indicate that, for many people with schizophrenia, brain development takes a different pathway from a very early stage, possibly even <em>in utero</em>.

The first noticeable symptoms of schizophrenia often emerge in the teen years and include anxiety, low mood, social withdrawal or preoccupation with odd beliefs. This description includes most teenagers at some point or other (and many adults too), so, once again, these features do not diagnose schizophrenia, although if they are present to a substantial extent, they might identify a young adult at increased risk of psychological or psychiatric problems. Early intervention programmes have been developed in many countries for this group, especially if they also misuse risky substances, such as cannabis. The shorter the duration of untreated illness, the better the outcome. Early interventions focus on many types of treatment, including psychological interventions, social support, and, if indicated, medication as well as family support.

<h3 class=”subheadMIstyles”>Clinical features of schizophrenia</h3>

The lifetime risk of schizophrenia is approximately 1 per cent and it is the condition most consistently associated with involuntary rather than voluntary psychiatric admission in Ireland and elsewhere. As a result, the issues raised by schizophrenia are not only clinical but also societal and legal. The most important issues raised by schizophrenia, however, can only be described in human terms relating to quality of life, altered opportunity for personal development, increased morbidity and mortality, and the suffering and stress of patients, family members and carers.

According to the World Health Organisation’s <em>International Classification of Diseases</em> (<em>ICD-10</em>), a diagnosis of schizophrenia requires either one major symptom or two minor symptoms that are present for most of the time during an episode of psychotic illness for at least one month, or else at some time during most of the days.

The major symptoms are: (a) Thought echo, thought insertion, thought withdrawal, or thought broadcast; (b) delusions of control, influence or passivity, referring to body or limb movements, or specific thoughts, actions, or sensations, or delusional perception; (c) auditory hallucinations of voices giving a running commentary on the person’s behaviour, or discussing the patient between themselves, or other hallucinatory voices coming from the body; and (d) other kinds of persistent delusions that are culturally inappropriate and completely impossible.

Minor symptoms include: (a) Persistent hallucinations in any modality, occurring every day for some weeks, accompanied by delusions (which may be fleeting) without clear mood-related content, or persistent over-valued ideas; (b) various kinds of thought disorder, such as neologisms, breaks or interpolations in thought, with resulting diminished coherence; (c) catatonic behaviour (eg, posturing or waxy flexibility, excitement, mutism, negativism, stupor); and (d) negative symptoms (eg, emotional blunting or incongruity, paucity of speech or marked apathy), which are not attributable to medication or depression. There may also be consistent and significant change in other aspects of behaviour (eg, social withdrawal).

In practice, presentations with schizophrenia vary greatly. One person might present with a long history of quiet, paranoid delusions that have finally become problematic for them, possibly after existing for many, many years. Another might present with a sudden onset of dramatic hallucinations commanding him or her to do certain things or go certain places; such commands might be resisted or ignored, but are usually either perplexing or distressing. Others might present with very vague symptoms, chiefly related to social withdrawal and self-isolation, and it might not be clear if the person is mentally ill, misusing drugs, or simply choosing to live differently. Sometimes, it is a mix of all three.

Given this enormous diversity of symptoms and clinical presentations, schizophrenia is one of the true enigmas of medicine and, possibly, of the human condition in general. This is partly because ‘schizophrenia’ is really a term used to denote a cluster of symptoms that tend to co-occur, rather than a biologically-defined entity. This places schizophrenia in sharp contrast to conditions such as diabetes, which is biologically defined though measurement of blood glucose, or brain tumours, which are diagnosed with brain scans. Diagnosis of schizophrenia is based entirely on symptoms and it is therefore not at all surprising that diagnostic criteria have changed considerably over past centuries, although the essence of the disorder has remained remarkably constant.

<h3 class=”subheadMIstyles”>What causes schizophrenia?</h3>

The causes of schizophrenia are not fully understood. The disorder probably results from a complex interaction of inherited genes, disruptions to brain development <em>in utero</em> and further contributory factors acting in childhood, adolescence and early adulthood.

To begin with, it is now well established that increased risk of schizophrenia runs in families. While no single gene has been proven to have a large effect for most people with schizophrenia, evidence from family studies is still very compelling. If a person has a first-degree relative with schizophrenia (eg, parent, sibling), their lifetime risk is increased from just under 1 per cent up to 15 per cent. Even if the person is reared apart from their family of origin (ie, adopted), their risk is still increased, at 12 per cent. If a person is a monozygotic twin and if one twin has schizophrenia, then the other twin has an approximately 50 per cent chance of developing the disorder.

These studies demonstrate two important facts: (1) There is a strong genetic element in risk of schizophrenia; and (2) other factors are equally important, such as environment, life experiences, and various other unidentified, apparently non-genetic influences. From the genetic point of view, there are likely to be multiple genes of moderate or small effect, which affect some but not all people at risk of schizophrenia. It is worth remembering, however, that despite these findings, most people with schizophrenia do not have a family history of the disorder, and most people with a family history do not develop schizophrenia. Therefore, while family history and genes certainly increase risk, other environmental factors are critically important too.

There is now strong research evidence that dopamine is not regulated correctly in schizophrenia although, given the highly interconnected nature of the brain, other brain chemicals are sure to be involved too. There are also certain abnormalities of brain structure in some people with schizophrenia, but none of these are sufficiently specific to schizophrenia to assist with diagnosing the illness, out-ruling it, or even identifying those at high risk.

There are, however, links between schizophrenia and injuries during pregnancy or at birth, season of birth (winter and early spring), psychological trauma in childhood, cannabis use, head injury, migration and social adversity. All of these factors are linked with schizophrenia to varying degrees but some of the risks are very small: for example, being born in winter or early spring seems to explain at most 3 per cent of the risk of schizophrenia, presumably due to infections during pregnancy: This is a tiny proportion of the risk and even this is still subject to debate.

It has long been recognised that there are more people with schizophrenia in urban areas (eg, cities) than in rural ones (ie, countryside). Studies in the 1960s and 1970s showed that the most obvious explanation for this turns out to be true, at least in part: People with pre-existing schizophrenia tend to drift into urban areas to seek assistance, accommodation and various other supports, leading to a relative concentration of schizophrenia in cities as a result of the disorder.

It soon became clear, however, that this ‘urban drift’ could not fully explain the association between schizophrenia and cities. Further research duly showed that, even after taking ‘urban drift’ into account, urban birth, urban upbringing, and urban living are all associated with increased risk of developing schizophrenia in later life. Just like having a family history of schizophrenia, however, living in cities is neither necessary nor sufficient for developing the disorder, although it does increase the lifetime risk from just under 1 per cent to just under 2 per cent (using best available estimates).

There must be some unidentified causal factor at work here, some biological or psychological feature of cities that alters brain development or function so as to increase risk of schizophrenia. Possible explanations include increased exposure to infections or air pollution in cities, or possibly vitamin D deficiency. But these theories, although logical, remain unproven.

Another possible explanation centres on what is best termed ‘community disorganisation’, and its social, psychological and biological effects on the brain. For example, it is known that migrants experience increased rates of many mental disorders, including schizophrenia, and this appears related to the size of migrant group in the host country: The smaller an ethnic minority group is, the greater its increase in risk of schizophrenia.

Many mental illnesses, including schizophrenia, are associated with disturbances of the body’s stress responses, as reflected in body cortisol, a steroid hormone produced in situations of stress.

Chronic production of high levels of cortisol damages all body systems, including the brain. It is highly probable that belonging to a small minority migrant and/or ethnic group is associated with a state of chronic stress, producing increased cortisol and therefore increased risk of schizophrenia. Childhood trauma and abuse might also act in the same way.

This kind of ‘stress effect’ is likely to be more powerful in urban areas, as city-living affects the brain’s response to stress. This ‘stress hypothesis’ is a compelling theory with much evidence to support it, but it is still a theory. And even if living in a city does increase risk in this fashion, it remains the case that the vast majority of people in cities do not develop schizophrenia and that the attributable risk is small. So even if all of these findings relating to cities, stress and the brain are borne out in further studies, schizophrenia will still remain, in large part, a mystery.

Ultimately, research in this area is greatly hampered by the fact that schizophrenia is defined by symptoms rather than biological tests.

It is worth reiterating that ‘schizophrenia’, like ‘headaches’ and ‘fever’, is almost certainly an umbrella term that covers a family of different but related sub-disorders, rather than a single entity. These sub-disorders, despite sharing certain symptoms, might well have somewhat different origins in different individuals, depending on various combinations of biological, psychological and social factors.

<h3 class=”subheadMIstyles”>Treatment and outcomes</h3>

Treatment of schizophrenia requires a biopsychosocial approach and NICE provides relevant recommendations in its review of ‘Psychosis and schizophrenia in adults: Prevention and management’. The NICE advice covers a range of areas but places especially strong emphasis on early intervention for first-episode psychosis, for which it recommends oral antipsychotic medication in conjunction with psychological interventions (eg, family interventions, individual cognitive behaviour therapy).

It is also recommended that the choice of antipsychotic medication is made by the patient and healthcare professional (and, when appropriate, carer) together, taking account of probable benefits and adverse effects of each option, including possible metabolic consequences (eg, weight gain), extrapyramidal side-effects (eg, dyskinesia), possible cardiovascular effects and hormonal changes. There is a broad range of antipsychotic medications available with different benefits and adverse effects, so there are many options to choose from.

For a small minority of patients, electroconvulsive therapy (ECT) may be indicated. NICE recommends ECT for severe depressive illness, prolonged or severe episodes of mania, or catatonia (which can occur in schizophrenia), provided certain conditions are met. ECT should be administered to gain fast, short-term improvement of severe symptoms after other treatment options have failed, or when the situation is life-threatening. Particular caution is advised in pregnant women and older or younger patients; an individual risk-benefit assessment should be performed (balancing adverse effects, such as memory problems, with benefits); and patients should be reassessed regularly during programmes of ECT.

In terms of outcomes, while schizophrenia is a treatable mental disorder, it is notable that life expectancy is considerably reduced: On average, men with schizophrenia die 15 years earlier, and women 12 years earlier, than the rest of the population. This is not explained by unnatural deaths; the leading causes are heart disease and cancer. As a result, there is a need for enhanced focus on the physical health of persons with schizophrenia, including support in stopping smoking, promotion of improved diet and lifestyle, and screening for cardiac risk factors.

<p class=”Bodycopynoindent”>In addition, treatment with antipsychotic medication reduces the likelihood of premature death, providing yet another reason to persist with treatment in this complex, misunderstood but treatable disorder.

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