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:

These symptoms are commonly called positive symptoms.

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.

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.

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:

Clozapine and refractory illness

Clozapine was developed as an antipsychotic drug during the 1960s. Unfortunately, use is associated with a 1–2% incidence of neutropenia and this initially resulted in the withdrawal of the drug from clinical practice. However, it was noted even at an early stage in the drug’s history that it was free of the extrapyramidal side frequently seen with the other antipsychotic drugs. In the 1980s, clozapine was demonstrated to have a greater efficacy than other antipsychotics (Kane et al., 1988; Lieberman et al., 1994) and was subsequently reintroduced into clinical practice but with routine monitoring of blood mandatory.

Clozapine is now established as the drug of choice in treatment-resistant schizophrenia but it is not without problems (Tuunainen et al., 2000). In addition to neutropenia, it is associated with a greater risk of seizures, particularly if doses are above 600 mg daily. Some guidelines recommend the co-prescribing of sodium valproate to reduce this risk. In addition, use is associated with excessive drooling, hypotension and sedation during the early stages of treatment, requiring slow dose increases initially.

A regimen of gradual dose increases starting at 12.5 mg twice daily aiming to reach 300 mg in 2–3 weeks is normally recommended. However, this rate of dose increase is frequently too rapid, with tachycardia being a particular problem. In such cases, it is usual to slow down the rate of dose increase to a half or a quarter of that recommended. Although tachycardia is a common problem with clozapine initiation, if use is associated with fever, chest pain or hypotension this may indicate a high risk of myocarditis and the drug should be stopped (Committee on Safety of Medicines, 2002).

Polypharmacy

Polypharmacy remains a matter of concern in the management of individuals with schizophrenia. It usually arises because:

Neuroleptic equivalence

Although antipsychotic drugs vary in potency, studies on relative dopamine receptor binding have led to the concept of chlorpromazine equivalents as a useful method of transferring dosage from one product to another. Concern has been expressed about the variation between sources for such values, in particular about the quoted chlorpromazine equivalents of the butyrophenones and the conversion of depot doses to oral doses (Table 30.2). Likewise, there is no agreement on the equivalent doses of the atypicals.

Table 30.2 Equivalence of typical antipsychotic drugs to 100 mg chlorpromazine (from Foster, 1989)

For research purposes the concept of proportion of the maximum dose stated in the British National Formulary (BNF) has been developed as a standardised method for calculating average doses used in practice. However, this may not be a useful way of determining a dose when transferring a patient from one antipsychotic to another.

Augmentation strategies and polytherapy

Schizophrenia is a complex illness with a very varied presentation. In addition to the core symptoms, elements of other mental illnesses such as mania, depression and anxiety may predominate. Controversy remains about whether these associated symptoms should be treated separately or as a part of schizophrenia. In addition, there is debate about whether these presentations represent an alternative diagnosis, for example, schizoaffective disorder when the mood disorder is a primary component of the presentation. The current fashion is for these components of the illness to be treated separately, with much resulting polytherapy with SSRI antidepressants and antiepileptic drugs for mood control.

In addition to the above, complex prescriptions can arise when treatment with clozapine is perceived to be inadequate or doses are limited due to side effects. The theory behind the addition of a further drug can be either that the plasma concentration of the clozapine will be enhanced by the addition of another drug, or the second drug will enhance a particular receptor blockade which may be considered necessary in a specific patient (Cipriani et al., 2009; Paton et al., 2007). The augmentation strategy with the best evidence to support its use is the addition of sulpiride or amisulpride to clozapine. Other strategies include the addition of risperidone, lamotrigine or Ω3 fatty acids. However, many of the trials that support these augmentation strategies are small scale and a meta-analysis concluded that no single strategy was superior to another (Paton et al., 2007).

Long-acting formulations of antipsychotic drugs

Most long-acting (depot) formulations, including the long-acting olanzapine formulation, are synthesised by esterification of the hydroxyl group of the antipsychotic drug to a long chain fatty acid such as decanoic acid. The esters which are more lipophilic and soluble are dissolved in an oily vehicle such as sesame oil or a vegetable oil (viscoleo). Once the drug is injected into muscle it is slowly released from the oil vehicle. Active drug becomes available following hydrolysis for distribution to the site of the action. A long-acting injection of olanzapine has been marketed which contains a salt of olanzapine and pamoic acid suspended in an aqueous vehicle. This also is designed for intramuscular injection every 2–4 weeks.

Although the ideal long-acting antipsychotic formulation should release the drug at a constant rate so that plasma level fluctuations are kept to a minimum, all the available products produce significant variations (Table 30.3). This can result in increased side effects at the time of peak plasma concentrations, usually after 5–7 days, for oil-based depots and increased patient irritability towards the end of the period, as plasma concentrations decline. For many patients though, oil-based long-acting formulations result in a very slow decline in drug availability after a period of chronic administration (Altamura et al., 2003). When transferring a patient from depot formulations to oral administration, it may be many months before the effect of the depot finally wears off.

Long-acting risperidone injection involves a microsphere formulation. The microspheres delay the release of risperidone for 3–4 weeks. Once release has commenced, the risperidone reaches a maximum concentration 4–5 weeks after the injection with a decline over the subsequent 2–3 weeks. This more rapid decline has an advantage that by 2 months after the last injection, little of the risperidone will remain. The delay in onset is often a reason for relapse as it is necessary to maintain oral supplementation for at least 6 weeks and this may be overlooked.

In addition to the principles of drug choice and dosage selection that apply to oral drugs, with depot therapy there is also a need to consider the future habitation of the patient. If the patient is to live an independent lifestyle, depot formulations are indicated, but if the person is to remain in staffed accommodation and receive other medicines routinely administered by a nurse, the use of depot formulations may not be logical.

Anticholinergic drugs

Anticholinergic drugs are prescribed to counter the EPSEs of typical antipsychotics, and at one time were routinely prescribed. It is generally accepted that, with the possible exception of the first few weeks of treatment with antipsychotic drugs known to have a high incidence of EPSEs, anticholinergic drugs should only be prescribed when a need has been shown. A number of studies have looked at the discontinuation of anticholinergic agents and reported re-emergence of the symptoms. Up to 60% of patients may be affected by re-emergence of symptoms and between 25% and 30% of patients will have a continuing need for anticholinergic drugs. The anticholinergic drugs are not without problems, having their own range of side effects that include dry mouth, constipation and blurred vision. Trihexyphenidyl in particular, is renowned for its euphoric effects and withdrawal problems can include cholinergic rebound. One of the benefits of the atypical antipsychotic drugs is the reduced need for co-prescription of anticholinergic drugs. However, EPSEs can still occur with atypical antipsychotic drugs, particularly at high dose.

Interactions and antipsychotic drugs

There are claimed to be many interactions involving antipsychotic drugs but few appear to be clinically significant. Propranolol increases the plasma concentration of chlorpromazine, and carbamazepine accelerates the metabolism of haloperidol, risperidone and olanzapine. When tricyclic antidepressants are administered with phenothiazines, increased antimuscarinic effects such as dry mouth and blurred vision can occur and most antipsychotic drugs increase the sedative effect of alcohol. The SSRI antidepressants fluvoxamine, fluoxetine and paroxetine interact with clozapine, resulting in increases in clozapine plasma concentration.

Therapeutic drug monitoring

Therapeutic drug monitoring is only of value if there is a reliable laboratory assay and a correlation exists between the concentration of the drug in any particular body compartment, usually blood/plasma, and its clinical effectiveness. Unfortunately, this is not the case for most antipsychotic drugs and the measurement of drug concentrations is not a part of routine clinical practice. In recent years, however, it has become common to measure clozapine levels although even with this drug there is only a weak correlation between plasma levels and clinical effect. The general guidance is that individuals who have not adequately responded to clozapine and have a plasma level below 350–500 µcg/L may benefit from a dose increase and those who suffer side effects and have a plasma level above this range may benefit from a dose reduction. Those with a plasma level above 1000 µcg/L are more likely to suffer seizures and cover using sodium valproate should be considered.

Adverse effects and antipsychotic medicines

There are a large number of adverse effects associated with antipsychotic medicines. Some of these effects, such as sedation, antilibido effects and weight gain may be considered to be of value with particular patients, but the susceptibility to such adverse effects is often a major factor in determining drug choice. Prescribing guidelines are available (Bazire, 2009; Taylor et al., 2009) which provide details of the relative likelihood of side effects with the various antipsychotic drugs. The major side effects are set out below.