Schizophrenia spectrum disorder is described as a debilitating, chronic, and relapsing brain disorder with complex symptomology. It manifests as a combination of positive, negative, and/or cognitive symptoms. The diagnosis of schizophrenia is associated with a 20% reduction in life expectancy, with up to 40% of deaths attributed to suicide.^1,2,3

According to the Diagnostic and Statistical Manual of Mental Disorders fifth edition, two or more of the following symptoms must be present for a significant portion of time during a one-month period:⁴

• Delusions
• Hallucinations
• Disorganised speech
• Grossly disorganised or catatonic behaviour
• Negative symptoms.

There must also be social/occupational dysfunction, while signs of disturbance must persist for at least six months.⁴

An overview of the symptoms associated with schizophrenia

Some patients may present with a number of concurrent positive and negative symptoms, while others only present with positive symptoms. Positive symptoms are the core feature of schizophrenia, said Prof Chiliza.⁵

The most common positive symptom is auditory hallucinations. Persecution is a common theme in schizophrenia, he noted. Patients often report that they hear voices discussing them or their whereabouts, plotting their downfall, or planning to harm them. Some patients also experience visual hallucinations.⁵

Negative symptoms include alogia (decreased thought and speech productivity), affective flattening (speech with little or no change to their tone, little or no change in their facial expression, even if they are talking about something upsetting or exciting), anhedonia (loss of ability to experience pleasure), avolition (decreased initiation of goal-directed behaviour) and a-sociality (social withdrawal, neglected activities of daily living reduction in motivation for social contacts). ^4,6,7,8,9

Neurocognitive and social cognition impairments are often under-recognised in patients living with schizophrenia, stressed Prof Chiliza. Neurocognitive impairments include for example slower thought processing speeds, inattention, poor vigilance and working memory, visual and verbal learning difficulties, reasoning, and problem-solving.^5,10

Social cognition refers to skills such as recognising emotion, understanding the thoughts and intentions of others, and interpreting social cues. Patients living with schizophrenia show significant impairments in social cognition, and these impairments are strongly related to functional outcomes. Treating social cognition yields significant improvements in real-world outcomes, including social functioning and social skill, explained Prof Chiliza.^5,10

Patients living with schizophrenia are also at high risk of mood and anxiety disorders and may also present with movement abnormalities (eg Parkinsonism and dyskinesia). Furthermore, noted Prof Chiliza, there is often an overlap in symptomology between schizophrenia, bipolar mood disorder (BMD), and schizoaffective disorder (ScAD).^5,11

As mentioned above, patients living with schizophrenia tend to have a number of positive symptoms, some depressive and almost no manic symptoms, while the predominant feature in patients living with BMD is mania. The latter patient population may sometimes present with some positive and depressive symptoms. Cognitive and negative symptoms are not associated with BMD. Patients living with ScAD have features of both schizophrenia and BMD.⁵

Another key feature of schizophrenia, and a major challenge in the management of patients, is anosognosia, or a lack of insight. A study by Phahladira et al assessed patient and clinician-rated changes in insight in acutely ill, minimally treated first-episode schizophrenia patients over 24 months of standardised treatment with a depot antipsychotic.^5,12

The study included 105 participants with first-episode schizophrenia, schizophreniform, or ScAD. Insight was assessed at baseline and then at six-, 12- and 24-months using the patient-rated Birchwood Insight Scale (BIS) and clinician-rated global insight item of the Positive and Negative Syndrome Scale (PANSS).¹²

There was a significant improvement over time for the PANSS insight item. However, the only significant improvement for the BIS was with the Need for Treatment subscale. There were no significant improvements noted for the Symptom Attribution and Illness Awareness subscales, as well as the BIS total score. Apart from depressive symptoms at baseline, there were no significant predictors of patient-rated insight.¹²

The authors cautioned that clinicians should be aware that, even when treatment is assured and response is favourable, fundamental impairments in patient-rated insight persist. The results of the study are surprising and concerning because these patients were adherent to treatment, said Prof Chiliza. This implies that even when patients are adherent to treatment, they still need to be managed carefully.^5,12

Living with schizophrenia: Patient perspectives

Sharing their experiences of living with schizophrenia, patients describe feeling extremely scared when they experience their first episode of psychosis. Some describe it as losing ‘the self’.^5,13,14

This notion of ‘the self’ means that we live our conscious life in the first person perspective, as a self-present, single, temporally persistent, embodied, and bounded (demarcated) entity, who is the subject of experiences. Following a first-episode of psychosis, patients report that it is as if they are no longer a part of this world – almost as if they are a ghost, a silhouette, or an alien from another planet. They feel that they have become almost non-existent and that things are no longer the way they used to be. Early interventions are therefore crucial, stressed Prof Chiliza.^5,13,14

Importance of early intervention

The majority of patients living with schizophrenia present in adolescence or early adulthood. With routine care, <20% of patients achieve full recovery after a first-episode of psychosis, and <33% achieve minimal age-appropriate employment or education. Early intervention has been shown to improve poor outcomes associated with usual care.¹⁵

The critical period of intervention is during the first two- to five-years following psychosis onset. Studies show that most of the clinical and psychosocial deterioration in patients living with schizophrenia occurs during this period, and is associated with a high risk of relapse, re-hospitalisation, and suicide. A 15-year follow-up study of first-episode, non-affective psychosis (in which 63% of participants were eventually diagnosed with schizophrenia) reported relapse rates of 43% (12 months), 55% (24 months), and 70% (60 months).^15,16

It is thus clear that we need a comprehensive approach to the management of early psychosis, stressed Prof Chiliza. Kane et al compared the outcomes of a comprehensive, team-based treatment approach, to usual community care (treatment determined by clinician choice and service availability),  following a first-episode of psychosis. The study duration was 24- months.^5,17

The team used the NAVIGATE model, a specialty care programme aimed at helping patients, who experienced a first-episode of psychosis, meet the broad range of their psychiatric and psychosocial needs. The NAVIGATE model includes four core interventions: personalised medication management, family psychoeducation, resilience-focused individual therapy, and supported education and employment.¹⁷

They found that NAVIGATE improved outcomes in patients with effects seen on length of time in treatment (23 vs 17 months), quality of life (QoL) including improvement in interpersonal relations, sense of purpose, motivation, curiosity, emotional and common object, and activity engagements, participation in work and school (more participants in the NAVIGATE group were either working or going to school at any time during each month), and symptoms (average rate of hospitalisation for psychiatric indications was 3.2%/month for NAVIGATE and 3.7%/month for those in the community care programme). Patients with shorter duration of untreated psychosis derived substantially more benefit.¹⁷

What antipsychotics are available and how effective are they?

Most guidelines recommend second-generation antipsychotics – with the exclusion of olanzapine – as first-line therapy. The choice of agent depends on its side effect profile and patient preference. Patients should be treated for at least four to six weeks to determine the efficacy of the selected antipsychotic.^5,18

The choice of antipsychotic should be based on shared decision-making, taking the following side effects into account:¹⁹

• Extrapyramidal (including akathisia, dyskinesia, and dystonia)
• Metabolic (including weight gain and diabetes)
• Cardiovascular (including prolonging the QT interval)
• Hormonal (including increasing plasma prolactin)
• Other (including unpleasant subjective experiences).

According to Leucht et al, the efficacy of antipsychotics has been questioned over recent years. The team conducted a comprehensive systematic review of all acute-phase placebo-controlled antipsychotic drug trials in schizophrenia since the introduction of chlorpromazine in 1953. Intramuscular formulations were excluded.²⁰

The study showed that a minimal response to treatment (defined as either at least a 20% PANSS/Brief Psychiatric Rating Scale [BPRS] reduction from baseline or a Clinical Global Impressions Scale [CGI] score indicating at least slightly improved) with an antipsychotic occurred in 51% of patients versus 30% in the placebo group.²⁰  

A total of 23% of patients in the antipsychotic group versus 14% in the placebo group had a good response (defined as either at least a 50% PANSS/BPRS reduction or a CGI rating of at least much improved). Positive symptoms improved more than negative symptoms and depression. QoL and functioning improved even in the short term.²⁰

What about safety?

The importance of side effects is rated differently by patients, caregivers, and clinicians. From a medical perspective, relapse, extra-pyramidal symptoms (EPS), diabetes, hyperprolactinaemia, and weight gain are most important, said Prof Chiliza.^5,20,21

From a patient and caregiver perspective, weight gain (patients can gain up to 20kg within a few weeks of starting treatment), sleeping disorders, and concentration difficulties are important.²²

Prof Chiliza stressed that the goal of treatment should be remission, and the most efficacious, safest and simplest treatment interventions should be prioritised. Subsequent interventions will be more complex, and multiple treatment options should be explored if necessary. Treatment decisions should always take patient preferences into account.⁵

When should therapy be escalated? Therapy should be escalated if the patient does not show improvement. Prof Chiliza stressed it is important to make sure a sufficient dose is prescribed for a sufficient time. Escalation options include increasing the dose, changing to another antipsychotic with a different mechanism of action, combining two antipsychotics, augmenting with drugs from other classes (eg lithium), or opting for electroconvulsive therapy.^5,23

So what are some of the unmet needs in schizophrenia treatment?

Despite the introduction of second-generation or atypical antipsychotics in the 1990s, their clinical management continues to be an unmet need. The introduction of second-generation antipsychotics was expected to lead to a breakthrough in the control of negative symptoms, but evidence suggests that these treatments have only a modest impact.²⁴

Thus, many patients are left with negative symptoms after their positive symptoms have been partially or completely controlled. Negative symptoms are divided into primary and secondary symptoms. Primary negative symptoms are thought to be intrinsic to schizophrenia, while secondary negative symptoms are caused by positive symptoms, depression, medication side effects, social deprivation, or substance abuse.^24,25

Additionally, the assessment of the negative symptom dimension has recently improved, but current expert consensus-based instruments diverge on several aspects and the boundaries with other illness components, in particular neurocognition and social cognition, are not well defined.²⁵

So, while existing treatment options are largely efficacious for psychotic symptoms, this efficacy is limited for negative symptoms and cognitive deficits which underlie the substantive disability in this illness. Because of the proven impact that negative symptoms have on patient well-being, functioning, and health-related quality of life, it is crucial that clinicians can detect and address these symptoms early.^24,26

There is no clear consensus on the treatment of negative symptoms. According to the American Psychiatric Association (2010) guideline there is no effective treatment for negative symptoms, while the British Association for Psychopharmacology (2011) recommends augmentation with an antidepressant. The World Federation of Societies of Biological Psychiatry (2012) recommends amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, or ziprasidone as well as augmentation with an antidepressant.^27,28,29

A number of predominant negative symptom studies have been conducted to address this unmet need in the management of patients living with schizophrenia. Krause et al reviewed 21 randomised controlled antipsychotic drug trials involving 3452 patients living with schizophrenia and either predominant or prominent negative symptoms. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms.³⁰

Their review revealed the following significant differences in the primary outcome:³⁰

• In patients with predominant negative symptoms amisulpride was superior to placebo, olanzapine was superior to haloperidol, and cariprazine (not yet available in South Africa) outperformed risperidone. Cariprazine, a novel, third-generation antipsychotic, is a dopamine 2/3 receptor partial agonist with a ~10-fold higher affinity for D₃
• In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone.
• Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms.

The authors concluded that amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms.³⁰

However, Prof Chiliza pointed out that although only amisulpride is approved (in Europe) for the treatment of predominantly negative symptoms, its efficacy is controversial.^31,32,33,34

Negative symptoms have a major impact on the QoL of patients living with schizophrenia, and differing from positive symptoms, are often associated with a limited response to pharmacotherapy. Newer studies suggest that cariprazine 3mg-6mg/day should be the preferred agent for the treatment of a first episode of psychosis, followed by amisulpride

50mg-300mg/day, quetiapine or olanzapine, and the addition of an antidepressant. In patients living with chronic or relapsing schizophrenia, second-generation antipsychotics are recommended, however, if patients do not show improvements, switching to cariprazine is a viable option.³⁵

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