Schizophrenia

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30 Schizophrenia

D. Branford

Key points

• Schizophrenia is a complex illness which varies greatly in presentation.
• Positive symptoms such as hallucinations, delusions and thought disorder, which commonly occur in the acute phase of the illness, usually respond to treatment with antipsychotic drugs.
• Negative symptoms such as apathy, social withdrawal and lack of drive, which occur commonly in the chronic phase of the illness, are more resistant to drug treatment.
• The term ‘atypical’ is used to describe the newer antipsychotic drugs that do not cause extrapyramidal side effects.
• The atypical antipsychotics are associated with a range of metabolic side effects including weight gain and diabetes.
• Typical antipsychotic drugs are often associated with anticholinergic, sedative and cardiovascular side effects in addition to extrapyramidal side effects.
• Long-term treatment with typical antipsychotic drugs is associated with the development of tardive dyskinesia.
• Most typical and atypical antipsychotic drugs have similar efficacy in the treatment of schizophrenia.
• Decisions about which antipsychotic drug to use should be a mutual decision based on an informed discussion involving individual preference, previous efficacy and side effects.
• Clozapine has a broader spectrum of activity than traditional antipsychotic drugs with some efficacy for treatment-resistant schizophrenia and negative symptoms.

The concept of schizophrenia can be difficult to understand. People who do not suffer from schizophrenia can have little idea of what the experience of hallucinations and delusions is like. The presentation of schizophrenia can be extremely varied, with a great range of possible symptoms. There are also many misconceptions about the condition of schizophrenia that have led to prejudice against sufferers of the illness. People with schizophrenia are commonly thought to have low intelligence and to be dangerous. In fact, only a minority shows violent behaviour, with social withdrawal being a more common picture. Up to 10% of people with schizophrenia commit suicide.

Classification

Since the late nineteenth century there have been frequent attempts to define the illness we now call schizophrenia. Kraepelin, in the late 1890s, coined the term ‘dementia praecox’ (early madness) to describe an illness where there was a deterioration of the personality at a young age. Kraepelin also coined the terms ‘catatonic’ (where motor symptoms are prevalent and changes in activity vary), ‘hebephrenic’ (silly, childish behaviour, affective symptoms and thought disorder prominence) and ‘paranoid’ (clinical picture dominated by paranoid delusions). A few years later Bleuler, a Swiss psychiatrist introduced the term ‘schizophrenia’, derived from the Greek words skhizo (to split) and phren (mind), meaning the split between the emotions and the intellect.

Two systems for the classification of schizophrenia are widely used: the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV; American Psychiatric Association, 1994) and the International Classification of Diseases, 10th edition (ICD 10; World Health Organization, 1992).

Symptoms and diagnosis

Acute psychotic illness

To establish a definite diagnosis of schizophrenia it is important to follow the diagnostic criteria in either DSM IV or ICD 10, but symptoms which commonly occur in the acute phase of a psychotic illness include the following:

• awkward social behaviour, appearing preoccupied, perplexed and withdrawn, or showing unexpected changes in behaviour
• initial vagueness in speech which can progress to disorders of the stream of thought or poverty of thought
• abnormality of mood such as anxiety, depression, irritability or euphoria
• auditory hallucinations, the most common of which are referred to as ‘voices’; such voices can give commands to patients or may discuss the person in the third person, or comment on their actions
• delusions, of which those relating to control of thoughts are the most diagnostic; for example, patients feel that thoughts are being inserted into or withdrawn from their mind
• lack of insight into the illness.

These symptoms are commonly called positive symptoms.

Factors affecting diagnosis and prognosis

There is a reluctance to classify people as suffering schizophrenia on the basis of one acute psychotic illness, but there are a number of features which aid prediction of whether an acute illness will become chronic. These features include:

• age of onset, which, typically for schizophrenia, is late teenage to 30 years
• reports of a childhood which indicate the individual did not mix or was a rather shy and withdrawn personality
• a poor work record
• a desire for social isolation
• being single and not seeming to have sexual relationships
• a gradual onset of the illness and deterioration from the previous level of functioning
• grossly disorganised behaviour

Treatment

There is a wide range of antipsychotic drugs available for the treatment of a psychotic illness. Although most antipsychotic drugs are equally effective in the treatment of psychotic symptoms, some individuals respond better to one drug than another.

There is controversy over how long people should remain on an antipsychotic drug following their first acute illness. Some would argue that, if the prognosis is poor, long-term therapy should be advocated. Others would want to see a second illness before advocating long-term therapy.

Chronic schizophrenia

Between 60% and 80% of patients who suffer from an acute psychotic illness will suffer further illness and become chronically affected. For these patients the diagnosis of schizophrenia can be applied.

As schizophrenia progresses, there may be periods of relapse with acute symptoms but the underlying trend is towards symptoms of lack of drive, social withdrawal and emotional apathy. Such symptoms are sometimes called negative symptoms and respond poorly to most antipsychotic drugs.

Causes of schizophrenia

Although the cause of schizophrenia remains unknown, there are many theories and models.

Vulnerability model

The vulnerability model postulates that the persistent characteristic of schizophrenia is not the schizophrenic episode itself but the vulnerability to the development of such episodes of the disorder. The episodes of the illness are time limited but the vulnerability remains, awaiting the trigger of some stress. Such vulnerability can depend on premorbid personality, the individual’s social network or the environment. Manipulation and avoidance of stress can abort a potential schizophrenic episode.

Developmental model

The developmental model postulates that there are critical periods in the development of neuronal cells which, if adversely affected, may result in schizophrenia. Two such critical periods are postulated to occur when migrant neural cells do not reach their goal in fetal development and when supernumerary neural cells slough off at adolescence. This model is supported by neuroimaging studies which show structural brain abnormalities in patients with schizophrenia.

Ecological model

The ecological model postulates that external factors involving social, cultural and physical forces in the environment, such as population density, individual space, socio-economic status and racial status, influence the development of the disorder. The evidence in support of such a model remains weak.

Genetic model

There is undoubtably a genetic component to schizophrenia, with a higher incidence in the siblings of schizophrenics. However, even in monozygotic twins there are many cases where only one sibling has developed schizophrenia.

Transmitter abnormality model

The suggestion that schizophrenia is caused primarily by an abnormality of dopamine receptors and, in particular, D2 receptors, has largely emerged from research into the effect of antipsychotic drugs. Such a theory is increasingly being questioned.

Other factors

Numerous other factors have been implicated in the development and cause of schizophrenia. These include migration, socio-economic factors, perinatal insult, infections, season of birth, viruses, toxins and family environment.

In reality, all of these factors may influence both the development and progression of schizophrenia. Social, familial and biological factors may lead to premorbid vulnerability and subsequently influence both the acute psychosis and the progression to chronic states. What is then likely is that the illness will feed back to influence social, familial and biological factors, thus leading to future vulnerability.

Drug treatment

Mode of action of antipsychotic drugs

Although the cause of schizophrenia is the subject of controversy, an understanding of the mode of action of antipsychotic drugs has led to the dopamine theory of schizophrenia. This theory postulates that the symptoms experienced in schizophrenia are caused by an alteration to the level of dopamine activity in the brain. It is based on knowledge that dopamine receptor antagonists are often effective antipsychotics while drugs which increase dopamine activity, such as amfetamine, can either induce psychosis or exacerbate a schizophrenic illness.

At least six dopamine receptors exist in the brain, with much activity being focused on the D2 receptor as being responsible for antipsychotic drug action. However, drugs such as pimozide, that claim to have a more specific effect on D2 receptors, do not appear superior in antipsychotic effect when compared to other agents.

Research into the mode of action of clozapine has caused a change of attention to the mesolimbic system in the brain and to different receptors. Clozapine does not chronically alter striatal D2 receptors but does appear to affect striatal D1 receptors. It also appears to have more effect on the limbic system and on serotonin (5HT2) receptors, which may explain its reduced risk of extrapyramidal symptoms. The term ‘atypical’ is used to categorise those antipsychotic drugs that, like clozapine, rarely produce extrapyramidal side effects (EPSEs).

Although the reason for the superiority of clozapine in schizophrenia treatment remains an enigma, a variety of theories have led to the development of a new family of antipsychotic drugs. Some mimic the impact of clozapine on a wide range of dopamine and serotonin receptors, for example, olanzapine, others mimic the impact on particular receptors, for example, 5HT2/D2 receptor antagonists such as risperidone, others focus on limited occupancy of D2 receptors, for example, quetiapine, while others focus on alternative theories such as partial agonism (aripiprazole).

Rationale for use of drugs

Although a variety of social and psychological therapies are helpful in the treatment of schizophrenia, drugs form the essential cornerstone. The aim of all therapies is to minimise the level of handicap and achieve the best level of mental functioning. Drugs do not cure schizophrenia and are only partially effective at eradicating some symptoms such as delusions and negative symptoms. At the same time, benefits have to be balanced against side effects and whether the need to suppress particular symptoms is important. For example, if the person has a delusion that he or she is responsible for famine in Africa, but this does not in any way influence that person’s behaviour or mood, a common view would be that there would be little point in increasing antipsychotic drug therapy. However, others would argue that this ‘untreated’ delusion would make the person stand out or be subject to social stigma and the delusion should be more aggressively treated. If, on the other hand, this delusion led to great distress, or violent or dangerous behaviour, then an increase in antipsychotic drugs would usually be indicated.

It is now accepted that antipsychotic drugs can control or modify symptoms such as hallucinations and delusions that are evident in the acute episode of illness. Except for clozapine and the other atypicals, there is little evidence for antipsychotic drugs being of value in the treatment of the negative symptoms, although the matter remains controversial (Chakos et al., 2001). Antipsychotic drugs increase the length of time between breakdowns and shorten the length of the acute episode in most patients.

Drug selection and dose

Over the years there have been many changes to the range of antipsychotic drugs available. Despite the availability of newer agents many of the issues relevant to drug selection and dose have remained similar for the last 50 years and include:

Individual response

Drug selection should not be based on chemical group alone, since individual response to a particular drug or dose may be more important.

Side effects

For older, typical antipsychotic drugs, side effects such as hypotension, extrapyramidal symptoms and anticholinergic effects are key factors in the choice of drug. In contrast, with the newer atypical drugs, side effects such as diabetes, sexual dysfunction and weight gain affect adherence in many patients. Sedation remains a factor for all antipsychotic drugs.

The key side effects of concern are those categorised as EPSEs. Those that caused these side effects were called typical antipsychotic drugs and those that did not were called atypical. This classification system, however, has always remained subject to criticism as some atypicals will cause EPSEs when used at higher doses and the side effects of the different atypicals can vary considerably. EPSEs include:

Akathisia or motor restlessness. This causes patients to pace up and down, constantly shift their leg position or tap their feet.

Dystonia is the result of sustained muscle contraction. It can present as grimacing and facial distortion, neck twisting and laboured breathing. Occasionally the patient may have an oculogyric crisis in which, after a few moments of fixed staring, the eyeballs move upwards and then sideways, remaining in that position. In addition to these eye movements, the mouth is usually wide open, the tongue protruding and the head tilting backwards.

Parkinson-like side effects usually present as tremor, rigidity and poverty of facial expression. Drooling and excessive salivation are also common. A shuffling gait may be seen and the patient may show signs of fatigue when performing repetitive motor activities.

Another movement disorder more commonly associated with typical antipsychotics is tardive dyskinesia. Tardive dyskinesia normally affects the tongue, facial and neck muscles but can also affect the extremities. Individuals with tardive dyskinesia often have abnormalities of posture and movement of the fingers in addition to the oral-lingual-masticatory movements.

Epidemiological studies support the association between the prescribing of typical antipsychotic drugs and the development of tardive dyskinesia. Other factors which also appear to be associated include the duration of exposure to antipsychotic drugs, the co-prescribing of anticholinergic drugs, the co-prescribing of lithium, advanced age, prior experience of acute extrapyramidal symptoms and brain damage. Many other factors have been postulated to be associated with tardive dyskinesia such as depot formulations of antipsychotic drugs, dosage of antipsychotic drug and antipsychotic drugs with high anticholinergic activity, but such associations remain unproven.

Although the mechanism by which tardive dyskinesia arises is unclear, the leading hypothesis is that after prolonged blockade of dopamine receptors, there is a paradoxical increase in the functional activity of dopamine in the basal ganglia occurs. This increased functional state is thought to come about through a phenomenon of disuse supersensitivity of dopamine receptors. The primary clinical evidence to support this theory arises because tardive dyskinesia is late in onset following prolonged exposure to antipsychotic drugs and has a tendency to worsen upon abrupt discontinuation of the antipsychotic drug.

Attempts to treat tardive dyskinesia have been many and varied. Treatments include use of dopamine-depleting agents such as reserpine and tetrabenazine, dopamine-blocking agents such as antipsychotic drugs, interference with catecholamine synthesis by drugs such as methyldopa, cholinergic agents such as choline and lecithin, use of GABA mimetic agents such as sodium valproate and baclofen, and the provision of drug holidays. Rarely are these strategies successful. Most successful strategies currently involve a gradual withdrawal of the typical antipsychotic drug and replacement with an atypical antipsychotic drug.

Concerns about the EPSEs and toxicity of typical antipsychotic drugs led to calls over the past 10 years for the ‘atypicals’ to be prescribed more widely. This approach was supported in national guidance which advocated that atypical antipsychotic drugs should be used for the treatment of a first illness. However, increasing concern about the side effects of the atypical antipsychotic drugs, which includes weight gain, diabetes and sexual dysfunction, has led many clinicians to question the benefits of the newer and more expensive atypical antipsychotics. In more recent guidance (National Institute for Health and Clinical Excellence, 2009), it has been advocated that:

• Oral antipsychotic medication should be offered to people with newly diagnosed schizophrenia.
• Information on the benefits and side effects of each antipsychotic agent should be provided and discussed with the patient.
• The decision as to which antipsychotic to use should be made in partnership with the patient and carer as appropriate.
• When deciding on the most suitable medication, the relative potential of the individual antipsychotics to cause EPSEs such as akathisia, metabolic side effects such as weight gain and other side effects including unpleasant subjective experiences should be considered.
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