The term Schizophrenia was coined by the Swiss psychiatrist, Bleuler in 1911. He was the first to describe the symptoms as ‘positive’ and ‘negative’. Over the decades doctors and scientists have made many advances that have led to standardisation of diagnostic criteria and patient management in order to ensure optimal outcomes. 

According to the World Health Organization, the schizophrenia disorders are characterised in general by fundamental and characteristic distortions of thinking and perceptions, and by inappropriate or blunted affect. Clear consciousness and intellectual capacity are usually maintained, although certain cognitive deficits may evolve in the course of time.¹ The life time risk of schizophrenia is approximately 1%. In Ireland, the Shine Organisation estimates that there are 39,000 people living with schizophrenia.² A Health Research Board report in 2011  highlighted schizophrenia as the illness with the second highest rate of admissions, accounting for almost 20% of all psychiatric admissions.³ In 2006 the estimated total cost of schizophrenia in Ireland was €460.6 million per annum. The direct cost of care was €117.5m and the burden of indirect costs was €343m. The cost of lost productivity due to unemployment, absence from work and premature mortality was €277m. Expenditure on indirect costs/informal care borne by families was €43.8m.⁴

To date no cure has been discovered for schizophrenia, however the disorder is highly manageable with antipsychotic medications and psycho-social therapies. The National Institute for Health and Care Excellence (NICE) has developed clear guidelines on the management of patients diagnosed with schizophrenia. These guidelines contain evidence-based recommendations for pharmacological, psychological and social interventions, emphasising collaboration between service users, professionals, families and carers.⁵

Aetiology

The aetiology of schizophrenia is believed to be multifactorial. Previous studies have reported genetic and environmental factors. Molecular studies have implicated certain genes, the most notable being: neuregulin (NRG1) on chromosome 8p21-22, which has a multiple role in brain development, synaptic plasticity and glutamate signalling); dysbindin (DTNBP1) on chromosome 6p22.3, which helps regulate glutamate release; DISC1 (disrupted in schizophrenia), which is a balanced chromosomal translocation that has multiple roles in synaptic signalling and cell functioning changes; and catecholamine O-methyl transferase (COMT) polymorphism, which helps regulate dopamine function in the frontal cortex. 

Environmental factors associated with an increased risk of schizophrenia include: complications of pregnancy, delivery and the neonatal period; delayed walking and neurodevelopmental difficulties; early social services contact and disturbed childhood behaviour; severe maternal malnutrition, maternal influenza and winter births; degree of urbanisation at birth; and use of cannabis, especially during adolescence.⁶

Imaging studies have identified structural changes including enlarged ventricles, especially the third and the lateral ventricles, hypoperfusion of the frontal cortex, widened sulci and narrow gyri, basal ganglia enlargement and smaller hippocampi and amygdalae.⁷

In terms of neurochemistry, a number of hypotheses have gained research interest over the past three decades. The main hypothesis is dopaminergic overactivity, which originated with the discovery that all effective antipsychotic medications that are dopamine (D2) receptor antagonists and dopamine-releasing agents, such as amphetamine, can produce paranoid psychosis.⁷ To date no consensus has been reached on the nature of the dysfunction and no conclusive evidence found that dopamine has a causal role in the disorder because most of the studies included patients who were already treated with dopamine D2 antagonists.^8,9

A further theory is that of excess serotonergic activity. 5HT2a/2c receptor agonists (lysergic acid diethylamide and psilocybin) can result in positive symptoms of schizophrenia in people who do not suffer from schizophrenia. Newer antipsychotics such as clozapine, olanzapine and risperidone are potent 5HT2a receptor antagonists. NMDA receptor antagonists (eg. ketamine, PCP) have been shown to induce both positive and negative symptoms of schizophrenia in healthy volunteers and exacerbate symptoms of patients with schizophrenia.⁶ Binding of PCP prevents glutamate from activating NMDARs, which suggests that the pathogenesis of schizophrenia may be caused by dysfunction of NMDARs in particular of the glutamatergic system in general. Unlike dopamine, the glutamatergic system is distributed throughout the brain and plays a prominent role in sensory processing and higher-level functions such as memory and executive functioning.¹⁰

Another hypothesis is that there are abnormalities of phospholipid metabolism in both brain and red blood cells. Clinical trials of treatment with omega 3 fatty acids have been undertaken. Emsley et al¹¹ published a review article in 2003 with case reports and other research supporting their use. An open label clinical trial reported efficacy of unsaturated essential fatty acids, in particular eicosapentaenoic acid (EPA), in treating schizophrenia. Emsley also reported that two out of four randomised controlled trials showed significant benefit with EPA as supplementation, on the positive and negative symptoms scale total scores.¹¹ 

Management of patients with schizophrenia

The current guidelines emphasise a patient centred approach focused on recovery and involving the patient, their families, carers and professionals. 

Antipsychotic medication

Chlorpromazine was discovered by the Rhône-Poulenc chemist Paul Charpentier in 1951 as a possible potentiator of general anaesthesia.¹² The use of chlorpromazine in psychiatry was first recognised by Henri Laborit, a surgeon and physiologist in the French army in 1952, and clinical investigations were conducted by Pierre Deniker at St Anne’s Hospital, Paris.^13,14

Since then a number of antipsychotic agents have been discovered and are currently classified into two categories: typical (first generation) and atypical (second generation) antipsychotics. 

The more commonly used typical antipsychotics include: chlorpromazine, haloperidol, perphenazine and fluphenazine. The more commonly used atypical antipsychotics include: risperidone, olanzapine, quetiapine, aripiprazole and paliperidone. 

Common side effects associated with antipsychotic medications are: drowsiness, dizziness, blurred vision, tachycardia, sensitivity to sun or menstrual problems for women. The typical antipsychotics can cause side effects related to physical movements – rigidity, tremors, persistent muscle spasms and restlessness, while atypical agents can cause major weight gain and changes in the patient’s metabolism such as a higher risk of diabetes or dyslipidaemia. 

Before starting antipsychotic treatments a patient should undergo baseline investigations: measurement of weight, waist circumference, pulse and blood pressure, fasting glucose and glycosylated haemoglobin, blood lipid profile and prolactin levels. Nutritional status, diet and level of physical activity should also be recorded as well as the presence of any movement disorders. Patients should have an ECG if it is specified on the summary of product characteristics, if they report cardiovascular risk factors or if admitted into hospital. Baseline investigations should be performed regularly and psychiatrists are provided with clear guidelines with regard to same by the NICE.⁵

Choice of medication depends on a patient’s initial presentation and baseline investigations. Response to treatment is monitored and the dose of antipsychotic medication can be increased to achieve symptom control. If the patient has not responded to optimum dose after a minimum of six to eight weeks, relapses despite medication adherence or experiences disturbing side effects, a switch to another antipsychotic should be considered. This choice can be either a first or second generation antipsychotic. 

Adherence to medication can be a barrier to determining response to treatment. The overall prevalence of suboptimal adherence among patients with schizophrenia ranges from one-third to two-thirds.¹⁵ In the UK, approximately 30% of patients are prescribed a long-acting injectable antipsychotic (LAI).¹⁶ The advantages of LAIs are improved bioavailability, more stable plasma levels, a wider window to reengage the patient if LAI is declined, earlier detection of non-adherence and reduced risk of intentional or accidental overdose.¹⁷

If optimal control is not achieved despite adherence to two antipsychotics, at least one a second generation agent, at a therapeutic dose for a minimum of six to eight weeks, the diagnosis is revised to ‘treatment resistant schizophrenia’. The gold standard management of treatment resistant schizophrenia is prescription of clozapine – a second generation antipsychotic that is shown to be effective in up to 60% of patients with treatment resistant illness.¹⁸ Those receiving clozapine undergo close monitoring for potential high-risk side effects including severe neutropaenia, and seizures, myocarditis and cardiomyopathy. 

Psychological therapies

A wide number of studies have been conducted to evaluate response to psychological therapies in patients with schizophrenia. One of the most researched forms of psychotherapy is cognitive behavioural therapy (CBT), which is recommended in conjunction with antipsychotic medication. A study by Turkington showed that brief CBT intervention along with psychoeducational material can be delivered with success by mental health nurses in the community with the help of carers, achieving symptomatic improvement without increased suicidality.¹⁹

NICE guidelines recommend family intervention in the form of single-family or multi-family group intervention alongside CBT, and suggest including the patient in the session if practical. The role of family intervention is to provide specific supportive, educational and treatment information, facilitate problem solving or enhance crisis management skills.⁵

Social interventions

Patients with schizophrenia tend to experience difficulties in social functioning and self-care, high rates of unemployment and social exclusion due to their symptoms and cognitive impairment.^20,21 A case control study by Foruzandeh and Parvin in 2013, analysed improvement in patient symptom scores based on their SAPS and SANS assessment/questionnaires. The group that received occupational therapy in addition to ‘treatment as usual’ showed a significant improvement compared to the group that did not receive occupational therapy input.²²

Social work intervention is also key to ensuring the needs of patients with schizophrenia are adequately addressed. Social workers focus on problem solving skills and coping skills as well as providing family and carer support. Patients may also need support in terms of accommodation and income. 

Other treatments

As briefly mentioned above in the aetiology section, research on glutamatergic dysfunction may lead to new biological treatments and bring hope to patients with schizophrenia.¹⁰

Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neurons. Clinical neuromodulation began in psychiatry as electroconvulsive therapy (ECT), but in recent years several new techniques have been developed including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), vagal nerve stimulation (VNS), trigeminal nerve stimulation (TNS) and deep brain stimulation (DBS).²³

According to available literature repetitive transcranial magnetic stimulation and transcranial direct current stimulation are the main treatment options evaluated for schizophrenia. Treatment protocols for schizophrenia generally involve ‘slow’ rTMS, specifically targeting and inhibiting auditory hallucinations, on the basis of a neurophysiological model of an overactive speech network during such phenomena.²⁴ Regarding tDCS, Mondino et al in 2015 outlined that tDCS might reduce auditory hallucinations and improve cognitive deficits.²⁵ Upon literature review, in Ireland to date, no studies have been published in relation to the use of neuromodulation in schizophrenia. 

Conclusion

Schizophrenia is an enduring mental illness, however with early diagnosis and appropriate treatment, symptoms can be successfully managed. Current guidelines published by NICE, the Irish College of Psychiatry and other bodies involved in the management of patients with schizophrenia emphasise a patient centred holistic approach, in order to ensure recovery and normal functioning. Biological therapy is best accompanied by psychosocial interventions. Biological therapies include the dopamine D2 antagonist antipsychotics while the glutamatergic theory and neuromodulation look promising in relation to the development of future treatment options. 

References

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