Schizophrenia: symptoms, diagnosis and treatment

Introduction

Schizophrenia is a chronic mental health condition with a lifetime incidence of 1% in the UK^​1​. People with schizophrenia often experience repeated episodes of psychosis, whereby they lose some contact with reality; for example, seeing or hearing things that other people cannot see or hear (hallucinations) and believing things that are not actually true (delusions). It may also involve confused (disordered) thinking and speaking. Psychosis occurs in several mental health conditions, including mood disorders (e.g. depression or bipolar disorder) and some neurological conditions (e.g. brain tumours or multiple sclerosis).

Patients with a diagnosis of schizophrenia have a life expectancy of 15–20 years below the national average^​2​. Although some causative factors directly relate to the illness, such as suicide, much of the burden owes to an increase in death from physical health complications, such as heart disease^​2​. The cost to the UK economy from schizophrenia is estimated at around £12bn per year^​3​.

Aetiology

Although the exact aetiology of schizophrenia is still not fully understood, there appears to be a genetic component involved. There is a high degree of heritability in schizophrenia and several variant genes have been linked to increasing the risk of developing schizophrenia^​4​.

However, genetics alone does not explain the incidence of schizophrenia and it appears that environmental factors also play a role, particularly stresses in early life^​5,6​. The use of drugs such as cocaine, cannabis and hallucinogens can also trigger the onset of psychotic symptoms in some patients^​7​. As a result, it is thought that a combination of these environmental factors with an underlying genetic susceptibility may lead to the development of schizophrenia in some patients^​8​.

Mechanisms involving changes in dopaminergic and glutamatergic transmission within the brain have been suggested, as has a reduction in the ability of the brain to adapt to changes (synaptic plasticity)^​9,10​. It has also been suggested that schizophrenia is actually a heterogenous group of conditions with similar symptoms but with different underlying mechanisms, which could explain the differences in symptomology and response to treatment^​11​. 

Diagnosis

A diagnosis of schizophrenia is made on the basis of symptoms reported by the patient. A health professional will usually carry out an interview with the patient about their experiences and talk to people who know the patient well. When considering possibly delusional beliefs, it is important to understand the reasons patients hold certain views. For example, a belief that one’s partner is having an affair wouldn’t necessarily be a delusional belief, unless the reasons for the belief were implausible and the level of belief could not be changed even with incontrovertible evidence. Personal, religious and cultural beliefs also must be taken into account^​1​.

Schizophrenia is characterised by repeated episodes of psychosis. The International Classification of Diseases 11th revision (ICD-11) criteria require at least two of the following symptoms to be present for at least a month for a diagnosis of schizophrenia, with at least one of the first four present^​12​:

• Delusional beliefs — these are fixed false beliefs that are held with such a conviction that they cannot be overturned even with uncontradictory evidence;
• Hallucinations — these are perceptions in the absence of any external stimulus. Most commonly these are auditory (e.g. voices) or visual but can occur in any of the senses;
• Disorganised thinking
• Experiences of influence, passivity or control — this means that the patient’s thoughts, feelings or actions are outside of their control; for example, that other people can read one’s thoughts or that thoughts have been implanted in one’s brain by someone else;
• Negative symptoms — these are symptoms similar to those of depression, such as flat mood, lack of energy and lack of enjoyment in activities. These can be confused with depressive symptoms, and 50% of patients with a psychotic illness also go on to develop a depressive illness^​13​. However, unlike with depression, patients with negative symptoms in the absence of depression present with no hopelessness or worthlessness;
• Grossly disorganised behaviour that impedes goal-directed activity;
• Psychomotor disturbances.

Since many patients lack insight into their illness, it is often family, friends and healthcare professionals who first identify psychosis in patients. Many people with a psychotic illness experience a prodromal period, where they have milder symptoms than in full psychosis^​14​. These symptoms could include hearing voices but being aware that they are not real, or having unusual beliefs but not holding them with the conviction of a true delusional belief. The prodromal phase is also usually accompanied by a reduction in social function, with patients becoming withdrawn and often finding it difficult to carry out their usual activities. Many mental health services offer help for patients in this prodromal phase, which is also known as ‘at-risk mental state’ (ARMS). This means patients can be monitored closely and treatment started as soon as psychosis develops. The National Institute for Health and Care Excellence (NICE) recommends that ARMS patients should have an assessment by a specialist, be offered cognitive behavioural therapy and be treated for any co-existing mental health conditions; however, at present, not all areas offer an ARMS service.

It is vital that psychotic illnesses are identified early in their development, since it has been shown that the duration of untreated psychosis is a key factor in a patient’s prognosis^​14​. Early treatment can prevent a disorder’s development into schizophrenia. In order to ensure patients who have a psychotic illness do not experience delays in treatment, specific ‘early intervention’ teams within mental health services have been set up with a remit to assess and treat patients suspected of a psychotic illness within two weeks of referral^​15,16​. Pharmacists should be aware of the signs of psychosis and the local pathway for referring into these teams: some services accept referrals from patients and relatives, whereas others only accept referrals from healthcare professionals.

Of course, not all patients who have a psychotic episode go on to develop schizophrenia. Since the long-term trajectory of the illness cannot be characterised when symptoms are first detected, there is usually a delay before a diagnosis of schizophrenia is given. Non-ICD-11 terms such as ‘first-episode psychosis’ are often used as placeholders until it can be determined whether an episode is a short-lived (for example in an acute and transient psychotic disorder). A diagnosis of schizophrenia is only made after prolonged or repeated episodes.

Patients with schizophrenia may also have a mood disorder, but the psychosis in schizophrenia is seen even when mood is euthymic; therefore, patients who only experience symptoms at the extremes of mood would not be diagnosed with schizophrenia^​12​. Psychotic-like symptoms can be seen with some organic diseases, such as dementia or following a head injury, and hearing voices is also commonly experienced by patients with post-traumatic stress disorder or borderline or antisocial personality disorder^​12​. Therefore, it is important to obtain a full history of a patient’s life to avoid inappropriate treatment. When symptoms can be better explained by other causes, a diagnosis of a psychotic illness would not be given but it is important to bear in mind that psychosis can be co-morbid with these conditions^​12​.

Pharmacological treatment

The mainstay of pharmacological treatment for psychotic disorders are antipsychotic drugs, with all the currently UK-licensed medicines being dopamine-D2 antagonists or partial agonists. Since all have a similar mechanism of action, the difference in efficacy between individual agents is small, with the exception of clozapine, which appears to have additional actions and will be discussed later^​17​. Therefore, the major differentiating factor between antipsychotic medications is the side-effect profiles.

Side effects

Since dopamine is found in other pathways in the brain, blockade of D2 receptors can cause unwanted side effects. 

Drug-induced movement disorders, known as extrapyramidal side effects (EPSEs), can be caused by dopamine blockade in the movement pathways in the brain. These disorders include tremor at rest (Parkinsonism), muscle spasm (dystonia), and a feeling of inner restlessness (akathisia). Newer drugs (e.g. olanzapine), which are also 5-HT2A antagonists, are less likely to cause these side effects than older drugs, as are the dopamine partial agonists aripiprazole and cariprazine^​18​. 

Traditionally, for example in the British National Formulary, antipsychotics have been classified as either ‘first-generation’ (‘typical’) or ‘second-generation’ (‘atypical’) based on the likelihood of causing EPSEs (see Table 1^​19​). However, in reality, the split is somewhat arbitrary and there is more of a spectrum of the ability to cause EPSEs rather than a true division: for example, amisulpride and sulpiride have very similar receptor profiles but are classified in different categories. Some references also refer to the partial agonists as ‘third generation’ since their mode of action is slightly different from that of other antipsychotics.

Where EPSEs are seen, an anticholinergic drug such as procyclidine can be used to reduce symptoms.

Dopamine is also associated with the regulation of prolactin release from the pituitary gland, and antipsychotics can lead to hyperprolactinaemia. For women, this can lead to menstrual changes, sexual dysfunction, breast changes, and reduced fertility, and there is an increased risk of osteoporosis later in life in both sexes^​20​. As with EPSEs, newer drugs that are also 5-HT2A antagonists are less likely to cause these side effects than older drugs^​21​.

Many antipsychotics also have actions at receptors other than dopamine receptors, which leads to them having additional side effects. These actions are summarised in Table 2^{​17,20,21​}.

Choosing an antipsychotic

NICE guidelines recommend that treatment should be based on patient preference, taking into account factors such as the acceptability of side effects, other medications a patient is taking and any physical comorbidities^​1​. 

It is important to recognise that different patients will have different attitudes towards side effects and so there is no recommended first-line treatment. For example, some patients may find the sedation from some antipsychotics helpful if they are struggling with sleep, whereas others may find this side effect distressing, as it prevents them from carrying out their usual activities. When patients are too unwell to make an informed decision about their treatment at the initiation of an antipsychotic, it can be useful to talk to family and others who know the patient to guide treatment choice, as well as considering any family history and current co-morbidities. For example, a patient who has a strong family history of type 2 diabetes mellitus might avoid a medication associated with weight gain, as this is likely to increase the risk of developing the condition^​1​.

As well as being available in oral form, some antipsychotics are available in a long-acting injection form. It is given between once a week and once every six months, depending on the drug and dose (see Table 3^​19​). This has the advantage that patients do not have to worry about remembering treatment and adherence can be monitored by healthcare staff. Patients have been shown to be less likely to relapse when on an injectable formulation compared with oral medication^​22​. Long-acting injections are often prescribed and administered in secondary care and so may not be included on a patient’s GP record. Therefore, it is important to ask about this when reviewing patients with schizophrenia.

Monitoring treatment

Generally, an antipsychotic should be trialled for at least four weeks before response to treatment is evaluated^​20​. Treatment does not always completely prevent symptoms but can reduce them to a point that patients are able to cope with them. In particular, the negative and cognitive effects of antipsychotics are usually less easy to treat than the positive symptoms of delusions and hallucinations.

If a patient does not respond to an antipsychotic, it is usual to increase the dose to the maximum licensed dose, or the highest dose a patient can tolerate, before trying a different antipsychotic^​1​. If a patient fails to respond to treatment with two different antipsychotics at an adequate dose for an adequate time frame, the patient is classed as ‘treatment resistant’^​1​.

Since many antipsychotics have cardiac and metabolic side effects, it is important that a patient’s physical health is also monitored. A pre-treatment echocardiogram, blood pressure, weight and waist circumference measurements, and blood tests for urea and electrolytes, liver function and diabetes are recommended. Pharmacists can have a role in ensuring this monitoring is carried out, and promoting the importance of these tests in ensuring medication is used safely. These are usually repeated 12 weeks into treatment and then on an annual basis. The Lester Tool provides a framework for physical health management and can be used by pharmacists to better support patients as part of the COREPlus20 initiative^​23​. Even though many antipsychotics have metabolic side effects, there is evidence to show that, overall, they reduce mortality^​24​.

Validated, patient-completed scales, such as the Glasgow Antipsychotic Side-Effect Scale (GASS), allow side effects to be screened for^​25​. These can be especially useful for identifying sexual-dysfunction side effects, which patients may find embarrassing to talk about in conversation.

Stopping antipsychotics

There is no firm evidence to guide the length of treatment after a first episode of psychosis, but NICE recommends continuing treatment for at least one to two years^​1​. Around a third of patients will make a full recovery from a first episode psychosis, with a further third going into remission^​26​. However, most patients with an established schizophrenia diagnosis will require lifelong treatment.

Patients often stop antipsychotic treatment on their own^​27​. This not only makes relapse more likely, it also tends to make subsequent episodes more severe and harder to treat^​28​. Pharmacists have a role in identifying patients who may be non-adherent with medication, for example, if it is not being ordered on a patient’s repeat prescription. The reasons patients stop medication are often multi-factorial^​29​ — the presence of side effects, lack of insight regarding being unwell, and lack of response to treatment can all influence the decision. Having a discussion with patients at this point and signposting them back to secondary mental health services for a treatment review may prevent a patient relapsing, if the opportunity is identified early on.

If the decision to stop an antipsychotic is made, evidence supports stopping the antipsychotic slowly over a few months to minimise the risk of relapse. Abrupt cessation is associated with a rapid onset of ‘rebound psychosis’^​30​. 

Treatment-resistant schizophrenia

‘Treatment-resistant’ schizophrenia is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of two different antipsychotic agents (including an atypical agent), prescribed for an adequate duration (typically four to six weeks)^​1​. In this patient group, clozapine is the treatment of choice and should be offered to patients at this point.

Clozapine has clear superiority in patients who fail to respond to other antipsychotics; however, it has a range of side effects that mean it is not used as a first-line treatment^​31​. Concern about these side effects means that clozapine treatment is often delayed until patients have tried multiple different non-clozapine antipsychotics and there is some evidence to suggest that delaying clozapine treatment in patients with treatment-resistant schizophrenia can lead to a worse prognosis^​31,32​.

In around 1% of patients, clozapine can cause neutropenia and agranulocytosis, meaning they are unable to fight off infections. This is most common in the first four months of treatment, but has been known to occur later. For this reason, all patients on clozapine are required to have weekly checks of neutrophils and white cell counts for the first 18 weeks of treatment; the frequency decreases to fortnightly after this and then every 4 weeks after a year. If the condition is identified, treatment must be stopped^​33​. These patients are then contraindicated from taking clozapine in the future. Even though patients are receiving regular blood tests, those presenting with features of an infection (e.g. sore throat, fever) should be referred for a blood test to rule out a low neutrophil count.

Clozapine also commonly causes constipation. It is critical that a patient’s bowel habit is monitored throughout treatment. There have been numerous cases of clozapine-induced constipation leading to serious gastrointestinal blockage and even death. Therefore, it is important that patients who are taking clozapine who present with constipation are managed assertively, with simulant laxatives (such as senna) and osmotic laxatives (such as macrogol) being the usual first choices^​22​.

Clozapine can also cause excess saliva to remain in the mouth of patients on clozapine (sialorrhoea). This is usually treated by administering an antimuscarinic drug, most often hyoscine hydrobromide, to reduce saliva production.

It can also cause postural hypotension, especially early in treatment. For this reason, a patient’s clozapine dose is titrated slowly over a few weeks during initiation. If a patient misses more than 48 hours of treatment, re-titration is also required, although this can sometimes be achieved more quickly than the initial titration, particularly if less than a week has passed since the last dose^​34​.

Despite these side effects, the fact that clozapine is effective in treating otherwise treatment-resistant schizophrenia means that patients who are eligible for it generally look on it favourably^​35,36​.

As with long-acting injections, clozapine is usually managed through secondary care mental health services, and so may not listed on a patient’s GP record. It is especially important that all healthcare professionals are aware of clozapine since patients often present to physical healthcare settings without tablets meaning re-titration may be needed, and clozapine itself can sometimes be the underlying cause for admission; for example, owing to neutropenia leading to infection or constipation leading to bowel obstruction.

More information can be found in ‘Case study: treatment resistant schizophrenia’.

Readers may also find these hospital and community pharmacy-based case studies useful in providing further context for the management of patients with schizophrenia who have concurrent conditions or factors that could impact their treatment.

Non-pharmacological treatments

Antipsychotics are the main treatment for schizophrenia, but they are often more effective in treating the positive symptoms of the illness than the negative and cognitive symptoms.

Cognitive behavioural therapy for psychosis (CBTp) is a tailored version of CBT that helps patients to establish links between their thoughts, feelings and actions and their symptoms. NICE currently recommends at least 16 sessions of CBT for patients with a psychotic illness^​1​. 

Family interventions, such as behavioural family therapy, are also recommended by NICE. These emphasise the role families play in supporting patients with a psychotic illness and look at improving communication between the patient and their loved ones^​1​.

Since there is evidence that medication is often ineffective, or may even worsen, the cognitive effects of schizophrenia, research is currently looking into whether non-invasive neuromodulation interventions may be effective in this area. Interventions such as transcranial magnetic stimulation and transcranial direct current stimulation are showing promising results in trials and may offer benefits in this traditionally difficult-to-treat set of symptoms^​37​.

Several new antipsychotics have also been recently developed that are not mainly dopamine antagonists. Pimavanserin and lumateperone are both primarily antagonists of serotonin 5-HT2A receptors and have been approved by the Federal Drug Administration in the US. Xanomeline-trospium is a combined muscarinic agonist and anticholinergic, which has shown promise in phase III clinical trials^​38​. If these are launched in the UK, they may offer alternatives to the currently available treatments for schizophrenia.