Treating Schizophrenia: Guideline Recommendations & Unmet Medical Needs

In this article series, we look at clinical guidelines from around the globe. For a feasible approach, we have chosen a sample of 24 international guidelines for this review on the management of schizophrenia. The purpose is not to make an in-depth comparison of all existing guidelines, but to highlight the areas of greatest overlap and considerable differences.

In summary

• There is broad consensus among guidelines for the use of antipsychotics in the treatment of positive symptoms of schizophrenia

• Treatment of negative symptoms and cognitive impairment associated with schizophrenia (CIAS) remains an unmet need, resulting in fewer guideline recommendations for these symptoms

• While current guidelines are informative, inconsistent recommendations and gaps in care exist, and should be considered by clinicians when developing treatment plans for patients

Schizophrenia has a heterogeneous presentation, including positive symptoms (e.g. delusions), negative symptoms (e.g. avolition), and cognitive impairments (e.g. memory deficits).^1,2 The heterogeneity between patients with schizophrenia necessitates individual treatment approaches,³ and choice of treatment is determined by illness acuity or severity; past treatment response; and ensuring a balance between medication efficacy and tolerability.² Clinical practice guidelines serve to inform clinicians, translating evidence into recommendations with the goal of achieving positive patient outcomes.² Here we review 24 schizophrenia guidelines from around the globe and discuss current recommendations for the management of schizophrenia. A sample of key recommendations is provided in Table 1.

There is broad consensus among guidelines for the use of antipsychotics in the treatment of positive symptoms of schizophrenia

All treatment guidelines express a consensus recommendation for the treatment of positive symptoms of schizophrenia with antipsychotics.^{4–8,10–14,16–18,22–31} Although the preferred antipsychotic varies, lower doses are generally recommended, and guidelines agree that side effect profile and patient preferences should be considered when making decisions regarding pharmacological treatment.^{4–8,10,12,14,16–18,23–25,27,29,31}

For first-episode psychosis, nearly half of the guidelines reviewed recommend the use of second-generation antipsychotics (SGAs) over first-generation antipsychotics (FGAs) due to the reduced risk of side effects^{4,10,12,13,22,25,27,28,30,31} while the remaining guidelines do not specify a preference for FGAs or SGAs or state that there is no evidence of differences in efficacy between the two.^{5–8,11,14,16–18,23,24,26,29}

Guidance is inconsistent regarding maintenance therapy in schizophrenia, which is likely due to insufficient data in this area, as well as conflicting results in existing meta-analyses evaluating maintenance of antipsychotic treatment.²

Some guidelines recommend continuation of the same antipsychotic medication and dose that achieved remission,^{5,6,12,16,22,23,25,31} while others recommend antipsychotic therapy at the lowest effective dose.^10,14,29 Remaining guidelines either do not provide specific guidance for maintenance therapy, or simply recommend the continuation of antipsychotic treatment without recommending specific drugs or doses.^{4,7,8,13,17,18,27} Notably, the Oregon Health Authority differentiates itself by recommending that HCPs consider a medication taper after 6 to 12 months of clinical stability, with the potential for maintaining the lowest effective dose, or discontinuing medication altogether.¹¹

Several guidelines discuss treatment-resistant schizophrenia, all of which recommend the SGA clozapine as first-line therapy.^{4–8,10–14,16–18,23,25,27,29–31} In addition, several guidelines recommend considering augmentation with electroconvulsive therapy (ECT) in patients who do not respond to clozapine.^{4–6,10,12,13,16,23,25,27,29,31}

Treatment of negative symptoms and CIAS remains an unmet need

One key gap in clinical guidelines for schizophrenia is definitive guidance pertaining to negative symptoms and CIAS, as noted by fewer organizations providing concrete recommendations for these symptoms, as well as an overall lack of consensus recommendations (Table 1). This may be explained partly by the fact that there are no pharmacotherapies indicated specifically for the treatment of either of these symptom domains.^32,33

Several guidelines reviewed provide information on the treatment of negative symptoms; however, the strength of recommendation and anticipated effects of therapies varies greatly. Psychosocial interventions—including psychotherapy, cognitive behavioral therapy, social skills training, arts therapy, psychoeducation, life skills training, supported housing and employment, and lifestyle modifications such as a healthy diet and exercise—are commonly recommended strategies for negative-symptom management.^{6,15,16,18,19,21,23,25,26,29,30} In addition, SGAs are recommended by several guidelines for the management of negative symptoms,^{4,21–23,28,31} with low-dose amisulpride being frequently named.^4,5,21,23 Notably, negative symptoms are the primary focus of the Polish guidelines, which include the newer antipsychotic cariprazine as a first-line option for predominant and persistent negative symptoms. This recommendation is based on randomized controlled clinical trial data, and is a point of differentiation from other guidelines.²¹

Of the 24 guidelines reviewed, 18 provide recommendations for the treatment of CIAS, but guidance varies greatly (Table 1). Nine guidelines recommend cognitive remediation therapy^{6,10,15,16,20,23,25,29,30} but only three give a strong recommendation^23,25,30 and one provides a weak recommendation.⁶  Three guidelines recommend antipsychotics for the treatment of CIAS; however, most acknowledge there is limited evidence supporting their use.^4,5,31 Other recommendations include optimizing pharmacotherapy; for example, discontinuing anticholinergics or other potential causative agents,¹² choosing SGAs over FGAs for their favorable cognitive profile,^12,20,22,27 and utilizing the lowest effective antipsychotic dose.¹⁷

While current guidelines are informative, inconsistent recommendations and gaps in the treatment landscape exist

While practice guidelines are intended to guide patient care, clinicians should note gaps in guidance provided and take these into consideration when developing treatment plans. For the treatment of schizophrenia, this gap lies in the lack of definitive guidance for the management of the negative and cognitive symptom domains. While many guidelines reviewed acknowledge these symptoms and highlight the importance of optimizing functional status and quality of life, the lack of approved medications for these domains creates a substantial barrier for patients suffering with schizophrenia and the clinicians who are treating them. With scientific advancement and understanding of the underlying pathophysiology related to the symptoms of schizophrenia, there is hope that future guideline developments and revisions will experience a broad consensus in the treatment approach for all symptom domains.

This document is for educational purposes and is not intended to replace approved clinical guidelines. Readers are advised to refer to their country-specific guidelines when making clinical decisions.

Further reading

• Correll CU, et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophrenia 2022;8:5.
  Systematic review of English-language clinical practice guidelines for the management of schizophrenia, with a focus on current recommendations for pharmacological management with antipsychotics.

• Vita A, et al. European Psychiatric Association guidance on treatment of cognitive impairment in schizophrenia. Eur Psychiatry 2022;65:e57.
  Provides a comprehensive meta-review of the current available evidence-based treatments for CIAS, including pharmacological treatment, psychosocial interventions, and somatic treatments.

• Maroney M. Management of cognitive and negative symptoms in schizophrenia. Ment Health Clin 2022;12:282–299.
  Provides a review of the most recent, clinically pertinent data on the pharmacological and non-pharmacological management of negative and cognitive symptoms of schizophrenia.

Guideline Digest: Schizophrenia. Connecting Psychiatry. Published May 2023.

SC-US-75159

SC-CRP-13571

April 2023