Royal Australian and New Zealand College of Psychiatrists (RANZCP) Guidelines on Schizophrenia – A Synopsis by Prof Castle

THE RECOVERY MODEL

One of the most important principles underpinning the guidelines was the endorsement of the Recovery Model, which espouses a whole-of-person approach to treating people, such that an emphasis is placed on their lived life in their particular context, rather than an exclusive or predominant focus on symptoms of mental illnesses itself (in the case of schizophrenia, delusions and hallucinations). [3]

An emphasis is also placed on shared decision making regarding choice of treatments, with both the patient and the clinician accepting the other has expertise and experience in this regard, and that making a fully informed decision together is the preferred mode of practice.

The reader is referred to the recent article by Alguera-Lara et al for a discussion about shared decision making in mental health. [4]

STAGING

An important conceptual starting point for the guidelines is the acceptance of a ‘staging’ approach upon which the guidelines are structured. [5]

The virtue of adopting this paradigm lies in one being able to reflect upon differential treatment approaches at defined illness stages, albeit the underpinning strategies of good care are applicable at all stages.

A down-side to the staging approach is that, unlike cancer, schizophrenia is hugely heterogeneous in terms of longitudinal trajectory.

Care must always be taken to not ‘give up’ and accept ‘so-so’ treatment response and functioning just because the person is in the later stages of their illness journey (rather nihilistically referred to by some authors as a phase requiring a ‘palliative’ approach).

ULTRAHIGH RISK STATES

There has been considerable controversy about the utility and veracity of the so-called ‘ultra-high risk’ construct as it pertains to schizophrenia. [6]

Suffice to say that the predictive validity is not great, even if the sampling frame is enriched to encompass only people who are help-seeking.

The better clinical studies suggest a ‘conversion’ rate to psychosis (note the conversion is broader that ‘schizophrenia’) is under 10%, begging many questions about whether any intervention at all, apart for ‘watchful waiting’ is appropriate in this group of individuals.

Certainly using antipsychotics is not endorsed, given their side effects burden. Careful psychological treatments can be supported and may assist the individual developing psychological resilience.

Initial excitement about the efficacy of omega-3-fatty acids (‘fish oil’) has waned after a failed large-scale replication of an initially positive but small study. [7]

EARLY PHASE SCHIZOPHRENIA

When the individual is manifesting distressing and disabling psychotic symptoms, antipsychotic treatment is of course warranted.

A careful discussion with the patient and (where appropriate) family members, is required, with an articulation of the pros and cons of the various available medications.

The guidelines outline the antipsychotics available in Australia (brexpiprazole, the newest dopamine partial agonist, is not included as it was not available at the time the guidelines were produced).

There is no good randomised controlled trial evidence separating the various available agents in terms of efficacy in early phase schizophrenia, so a general guiding mantra is ‘first do no harm’ in the sense of not using agents which might cause side effects unnecessarily.

To my mind, newer so-called ‘atypical’ drugs are generally preferred due to their lower overall burden of extrapyramidal side effects (EPSEs), notably tardive dyskinesia (TD). For a full discussion about EPSEs, see the Psychscenehub review on EPSEs and the article on tardive dyskinesia.

A useful recent meta-analysis  bears out the lower overall risk of TD associated with most atypical agents, compared to older ‘typical’ drugs, albeit the typical and atypical distinction is perturbed by marked similarities (mostly in terms of dopamine D2 receptor blockade) and differences (in terms of many other receptor actions, including at various other dopamine receptors, serotonin receptors, muscarinic and histaminergic receptors) amongst these drugs. [8]

Read more about the mechanisms of actions of antipsychotics.

Note the newer agents lurasidone and brexpiprazole were not included in the meta-analysis, but data suggest they would have a relatively low risk of TD: indeed, brexpiprazole does not upregulate the dopamine D2 receptor so should have placebo-level TD risk, similar to aripiprazole. The receptor profiles of lurasidone and brexpiprazole are covered in this article.

HYPERPROLACTINAEMIA

The second side effect of potential concern is hyperprolactinaemia.

The atypical medications that most predictably raise prolactin are amisulpride, risperidone and paliperidone.

Amisulpride is a pure dopamine D2/D3 antagonist, and as dopamine is prolactin inhibiting factor, it is hardly surprising that post-synaptic blockade of dopaminergic tracts in the tuberoinfundibular pathway causes hyperprolactinaemia.

Risperidone and paliperidone raise prolactin levels more than other agents with a similar ratio of dopamine D2: serotonin 5HT2A receptor blockade.

This is in part at least explicable by the fact that they are not lipophilic so do not readily cross the blood-brain barrier and thus have relatively high serum levels; as the pituitary sits outside the blood-brain barrier, the pituitary is ‘vulnerable’ to the effects of these high levels.

There is some debate about whether hyperprolactinaemia in and of itself is any cause for concern.

Some people suggest one only worries if it is associated with problems such as menstrual disturbance, sexual dysfunction, galactorrhoea or breast engorgement.

I beg to differ because:

1) patients often do not divulge such sensitive side effects unless asked directly (and often clinicians do not ask); and

2) there is to my mind good evidence to support an effect of high serum prolactin on bone mineral density, with ensuing osteopaenia and risk of fractures.

This compounds the other risk factors for poor bone health carried by many people with schizophrenia, including poor diet, low vitamin D and calcium intake and low levels of high-impact exercise.

A third consideration is a possible association between hyperprolactinaemia and breast cancer, albeit this has not been shown consistently across studies.

Again, I would ask why one would risk a raised prolactin is one had other choices in terms of antipsychotics.

If one believes that the risks of raised prolactin are outweighed by the benefits of a particular antipsychotic, one approach is to add a partial dopamine agonist (aripiprazole, brexpiprazole).

An approach to hyperprolactinaemia associated with antipsychotics is shown below [9]

The involvement of a competent endocrinologist colleague is highly recommended.

METABOLIC SYNDROME AND PHYSICAL HEALTH

The third and perhaps most important side effects in terms of impact on physical health and longevity is the metabolic risk profile.

The physical health of people with schizophrenia and their reduced life expectancy consequent largely upon cardiovascular risk is a significant focus of the guidelines.

The diagram below presents a synopsis of the metabolic monitoring suggested for all patients starting an antipsychotic. [1]

Of course, monitoring is not enough in itself and needs to be combined with active interventions to ameliorate metabolic risk, including:

• Dietary advice: a dietician with experience working with the mentally ill can be very helpful;
• Regular exercise: an exercise physiologist can assist, and peer workers have a significant potential role to play;
• Limited alcohol intake: alcohol is full of carbohydrates and stimulates appetite through inhibition of gluconeogenesis.

Weight gain can occur with any of the antipsychotics, but is much more common with clozapine and olanzapine; quetiapine and risperidone carry intermediate risk, and ziprasidone, asenapine, lurasidone, aripiprazole and brexpiprazole carry the lowest risk. See Prof Correll’s video on metabolic and cardiovascular risks with antipsychotics. (Password required)

These risk profiles are mirrored largely by a propensity to dyslipidaemia and also diabetogenicity. The latter is driven not just by weight gain and increasing abdominal adiposity, but also by direct effects on the insulin cascade: this is most pertinent for olanzapine and clozapine.

Again, the question one needs to ask is why one would inflict extra cardiovascular risk on people who are already vulnerable, through the choice of a metabolically high-risk agent.

Pleasingly, the guidelines do suggest not using olanzapine ‘first line’: I would relegate it to the third line, personally; and of course clozapine is always reserved for treatment resistance (see below).

Should a chosen antipsychotic result in significant weight gain, despite the general strategies outlined above, consideration should be giving to switching to a more ‘metabolically friendly’ agent.

Of course, the potential risk of relapse of psychosis needs to be discussed in full with the patient, and the switch strategy needs to be carefully orchestrated.

If a switch is clinically contraindicated or otherwise undesirable, a number of adjunctive pharmacological approaches can be employed, as shown in the diagram below. The reader is also referred to the Psychscenehub review on Understanding and Managing Obesity in Mental Health.

MAINTENANCE TREATMENT AND PROBLEM OF ADHERENCE

As with any chronic illness requiring long-term treatment, many people with schizophrenia do not always take their medication as directed by their doctor. In people with schizophrenia, sub-optimal adherence to medication is compounded by numerous factors. [10]

As multifaceted are the causes of suboptimal adherence to treatment, so need be the strategies to address it.

A simple first step is to discuss openly and honestly the rationale for medication, and open up a dialogue about the pros and cons of the various options. This is part of the shared decision-making approach described above and is empowering to the patient.

Continually ‘checking in’ with the patient about how the medication is working for them and any side effects they are experiencing, is important in terms of engagement and messaging about it not being a ‘set and forget’ issue but one which can be a subject of ongoing dialogue.

Simple suggestions about how to deal with common side effects should be made available to the patient: for a good example, see the St Vincent’s Hospital (Melbourne) Patient and Carer Psychiatric Medication booklet. Click the image below to begin the download.

Dose changes, medication changes and the addition of other medication to ameliorate side effects (e.g. anticholinergics for Parkinsonism) should also always be ‘on the table’.

Adherence can also be enhanced by the simplification of medication regimes and the linkage of medications to certain structured daily events such as brushing teeth.

The use of dosette boxes and Webster packs can also assist remembering to take their medication at the time and dose prescribed.

Finally, consideration should be given to the use of long-acting injectable (LAI) forms of antipsychotic medications.

Research has shown that use of LAIs can reduce relapse and rehospitalisation in people with schizophrenia, but there are many barriers to their use, often more so from the prescriber than the patient.

The guidelines advocate for offering use early in the illness course, and I would strongly endorse this, expressly in those patients who have a high loading of risk factors for non-adherence.

PSYCHOSOCIAL TREATMENTS

The guidelines correctly and unambiguously advocate strongly for a holistic framework of care to be adopted and agreed (as far as feasible) with the patient and significant others, for the longitudinal management of schizophrenia.

The early and ongoing involvement of family members should be routine practice unless there is a specific reason against this.

The evidence-base for specialised family therapy interventions for schizophrenia is strong, notably for interventions informed by the ‘high expressed emotion’ literature: this reflects a style of family interaction characterised by three main elements, namely hostility, critical comments, and over-involvement.

Of course, the recognition of such patterns should not lead to a blaming of family members, but rather a respectful and sympathetic offer of help.

Regrettably, in Australia, the ability to offer family interventions as part of routine care is limited in public mental health services, but specialist services are available in some jurisdictions.

A range of psychological and psychosocial treatments have either a proven or emerging evidence base for efficacy. Those covered in the guidelines are summarised in the diagram below.

Some of these are well established and offered in many jurisdictions (e.g., cognitive behaviour therapy, cognitive remediation) and others are more ‘niche’ and require further research and evaluation (e.g., Open Dialogue).

A particular aspect of the lives of people with schizophrenia that is too often forgotten or at least not adequately addressed is that of vocation.

Employment rates amongst people with schizophrenia and Australia and New Zealand remain pathetically low (around 20% in Australia), and every effort should be made to deploy appropriate psychosocial strategies (notably cognitive remediation) to assist them to attain and retain work.

The benefits of work are myriad, including social inclusion, reduction in stigma, the establishment of routines, meaningful contribution to society and financial enhancement.

Peer workers, who have had the ‘lived experience’ of mental illness are increasingly common in mental health services, and this is again strongly supported in the guidelines.

Peer workers should not be seen as a replacement for clinical staff or simply a strategy for services to save money. They need to be integrated into the workforce, offered excellent training and supervision and ongoing support.

MANAGING ACUTE BEHAVIOURAL DISTURBANCE IN SCHIZOPHRENIA

For those of us working in acute psychiatry – and particular in public sector psychiatry – the clinical reality of aggression and violence in the workplace is such that having an agreed treatment response is vital, for the safety of all concerned.

The guidelines are here quite clear, with a staged approach to pharmacotherapy bolstered by excellent nursing interventions and using restraint and seclusion only if necessary. Pharmacotherapy approaches are summarised in the diagram below.

A detailed description of the protocol is covered in the article on the assessment and management of methamphetamine addiction.

It is important to remember always to try to understand the reasons behind aggression (often, in people with schizophrenia, it is driven by fear) and to investigate and treat underlying organic factors.

Depending on the level of arousal and the amenability of the patient, oral medications should be offered before resorting to the intramuscular route.

Intravenous administration of medication is not usual in mental health settings (mostly for safety reasons) but is very common in emergency departments.

Note that we advocate olanzapine as the ‘preferred’ antipsychotic and lorazepam as the ‘preferred’ benzodiazepine.

Olanzapine is a widely used agent which has the virtue of being available in oral (including wafer, which is very helpful in the acute phase due to rapid absorption and preclusion of not being able to ‘cheek’) and parenteral forms.

Dosing is straightforward, and the sedative properties are helpful. There are important caveats, though.

First, parenteral olanzapine cannot be administered within 2 hours of a parenteral benzodiazepine. But most important is the ‘prn’ use of olanzapine in short-term acute use should not mean it gets used for ongoing treatment unless that is the clearly articulated intention.

Far too often patents are discharged from acute care on olanzapine and gain a substantial amount of weight and manifest other markers of the metabolic syndrome, but the community team are too concerned about relapse, to switch to a more metabolically benign agent.

Thus, the preferred practice is to phase out the olanzapine before discharge from hospital (or at least on a reducing trajectory) with the intended longer-term antipsychotic (see above) being brought up to full dose.

Lorazepam is the preferred benzodiazepine due to its efficacy and intermediate half-life. The parenteral formulation requires refrigeration, and there are administrative issues regarding its use, as a ‘special access’ formulation.

Note also that we advocate for droperidol should olanzapine fail or the level of arousal is extreme, and expressly if it is associated with stimulant drugs (most worryingly ice).

This return to a ‘typical’ antipsychotic may seem odd in this day and age, but it just seems to have the edge over newer drugs in this scenario. And there are randomised controlled data to support this view. [11], [12]

Of course, care needs to be taken to assess and treat any emergent extrapyramidal side effects: akathisia can be distressing and lead to further agitation in an already distressed patient, and dystonias can be painful and scary (remember laryngeal dystonias, which can be fatal).

Concern about cardiac problems associated with QTc prolongation with droperidol have been overstated in the past, but obtaining an ECG as soon as feasible would be considered sensible, and of course, avoid the drug if there is a history of cardiac conduction problems, or the patient is on other medications that could prolong the QT interval.

TREATMENT RESISTANCE AND THE USE OF CLOZAPINE

Regrettably, many people with schizophrenia continue, despite modern treatments and early intervention strategies, to have a sub-optimal course of illness.

Some of the factors associated with such an outcome are not able to be ameliorated (for example, early illness onset, male sex, poor premorbid social and intellectual functioning, prominent negative symptoms at illness onset, long insidious prodrome).

But optimal holistic care and attention to longitudinal support can assist people to live a better life.

A major factor associated with poorer outcomes (both physical as well as mental) in schizophrenia is the use of drugs of abuse: cigarettes, alcohol and cannabis are the most commonly used in Australia, but stimulants are on the rise, and crystal methamphetamine is particularly pernicious and is associated with aggression, violence and criminality.

Our field is still struggling to understand and address these issues adequately, and evidence for effective interventions is lacking.

More broadly, the scientific community has been grappling with the definitional framework of ‘treatment resistance’.

A recent international collaborative (Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) – published after the writing of the RANZCP guidelines – has produced suggested criteria for treatment resistance, summarised in the table below. [13]

Approaches to treatment resistance need to evaluate the individual in their particular context.

To meet TRRIP criteria, two antipsychotics need to have been tried at a dose and for a duration that should be effective.

Here inter-individual variation in metabolism plays a part, but more importantly adherence to the medication must have been assured. Arguably, to ensure the latter a trial with an LAI is required, but this is not stipulated in most guidelines unless there is clear evidence of suboptimal adherence.

Response according to the guideline is as below.

The place of clozapine in treatment resistance is unassailed, even after all the decades since its advent. Some commentators suggest we tend to use clozapine too sparingly and not early enough in the illness course. Read more on the delay in starting clozapine and why it matters.

The added advantage of reducing suicidality adds weight to this argument, but the metabolic side effects (see above) and sedation and cardiac and other side effects (eg. blood dyscrasias, cardiomyopathy, myocarditis) need to be brought into the decision-making about the initiation of clozapine.

And of course, clozapine does not work for everyone, leaving very few other options with any robust clinical trial evidence.

CONCLUSION

RANZCP Guidelines for the Treatment of Schizophrenia and Related Disorders serve as a useful and reasonably comprehensive and up-to-date summary of the state of play regarding the treatment of this group of disorders.

The information provided here is rather selective and does not do justice to the breadth of the guidelines, especially as they pertain to ‘special groups’, including Aboriginal and Torres Strait Islander people of Australia, Maori and Pacific Islander peoples in New Zealand, women, the elderly and forensic populations.

The interested reader is referred to the original document for coverage of these topics.

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