Schizophrenia is an umbrella disease that covers several overlapping subtypes. We currently manage this in the clinic with a ‘trial and error’ approach until an acceptable treatment is found as no consistently useful biomarkers have been identified.
A recent systematic review led by Stephen Leucht aimed to quantify the efficacy of different antipsychotics in the following subgroups, compared to the general population of schizophrenia patients:
- first-episode patients
- children and adolescents
- Patients with predominantly negative symptoms
- patients with ‘treatment-resistant’ schizophrenia
- patients with comorbid substance use
- Elderly patients (>65 years).
If an antipsychotic is equally effective in a subgroup as in the general schizophrenia population, then studies (and clinical decisions) in the general schizophrenia population can be applied to the subgroup. This is desirable as many more studies have been conducted on the general schizophrenia population.
Pairwise meta-analysis and subgroup tests of RCTs were used by the authors. No exclusion criteria based on age, sex, race or diagnosis were used.
The general schizophrenia population was composed of patients who do not belong to a specific subgroup and are usually included in registrational studies, usually adults with chronic schizophrenia aged 18 to 65 years with an acute form of positive symptoms.
The analysis included all studies on second-generation antipsychotics in Europe or the United States and a selection of first-generation antipsychotics. Injectable formulations were excluded.
The primary outcome was change in overall symptoms of schizophrenia, as measured by rating scales.
The authors’ comprehensive search identified 537 RCTs that included 76,382 participants, of whom 34.9% were female and the mean age was 37.3 years (mean, range 7.9 to 80.2). The studies spanned regions including Africa, Australia, the Middle East and Asia, but most (64%) were located in Europe and North America. Study Breakdown:
- General schizophrenia population: 412 RCTs
- First-episode patients: 20 RCTs
- Children and adolescents: 25 RCTs
- Patients with major or major negative symptoms: 20 RCTs
- Patients with ‘treatment-resistant’ schizophrenia: 42 RCTs
- Patients with comorbid substance use: 13 RCTs
- Elderly patients (>65 years): 11 RCTs
Of the 507 random-effects subgroup tests performed, 46 (9%) showed an important distinction (p<0 05) between subgroups, but there was no clear indication of which drug should be used in which subgroup.
Overall, results where findings in the general population may not apply to subgroups include:
|amisulpride vs olanzapine||equivalent in sz zen pop||Olanzapine is more effective in NegSym|
|olanzapine vs asenapine||Olanzapine is more effective in SZ Gen Pop||Equivalent in NegSym|
|risperidone vs cariprazine||Risperidone is more effective in SZ Gen Pop||Equivalent in NegSym|
|clozapine vs chlorpromazine||equivalent in sz zen pop||Trizapine is more effective in treating|
|clozapine vs haloperidol||Clozapine is more effective in SZ Gen Pop||Equivalent in Paeds and NegSym|
|haloperidol vs fluphenazine||equivalent in sz zen pop||Haloperidol is more effective in PADs|
|olanzapine vs haloperidol||Olanzapine is more effective in SZ Gen Pop||Equivalent in Paeds, Subs and NegSym|
Key: NegSym: patients with negative symptoms, Paeds: children and adolescents, Sub: patients with comorbid substance use, SZ Gene Pop: general schizophrenia population, TreatRes: patients with ‘treatment-resistant’ disease.
The authors concluded:
The effects of antipsychotics in different patient subgroups were generally similar to those in the general population of patients with schizophrenia, but few studies compared the contribution of subgroups, particularly in terms of side-effects. If the evidence for treatment in a given subgroup is small, guideline makers and clinicians should consider using the results in a study cohort better suited to the general population of patients with schizophrenia.
strengths and limitations
The primary strength of this paper is its sheer size; This includes more than 76,000 patients and almost all available antipsychotics. Furthermore, the focus on important subgroups (eg, children, adolescents and older patients) that are often neglected is an exceptional feature of this research.
As the authors say, their research is limited by heterogeneity within each subgroup (for example, the definition of ‘treatment resistance’ varied by study). Furthermore, the study did not find consistent patterns across drugs or subgroups; Most notably for clozapine, which would be expected to be consistently better than other antipsychotics.
Furthermore, the authors use the general schizophrenia population as the basic comparator and treat it as a majority subgroup. However, it may be composed of even more subgroups, some of which are presented in this study. This can dilute the findings and make them less robust. Results were focused on finding up to 3 months – while this is widely accepted in the literature, its clinical utility is limited. Long-term data would be far more useful for clinical decision making.
Implications for Practice
The authors present an interesting study that attempts to support clinical decision making in important patient subgroups. Overall, they show that the data do not support an individualized treatment approach, where treatment is matched to patient subtype. Pharmacologically, this may be because the drugs have global effects on different receptor types and subtypes, undermining any apparent effect on the defined subtype of the disease.
Personally, I am of the view that the foundation of the study presents inherent challenges to this approach. As previously stated, schizophrenia may be a collection of diseases, an umbrella term for what has been described at the genetic level by Arnedo et al. (2015), and the proteomic level by Guest et al. (2013). Therefore, collecting data based on direct symptoms does not consider biological differences between patient subtypes, and may not have the potential to show the differences we would like to see.
Leucht S, et al. Response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis. Lancet Psychiatry. 2022 Nov;9(11):884-893. DOI: 10.1016/s2215-0366(22)00304-2.
Arnedo J, et al. Unraveling the hidden risk architecture of schizophrenia: confirmation in three independent genome-wide association studies. Am J Psychiatry. 2015 Feb 1;172(2):139-53. DOI: 10.1176/api.ajp.2014.14040435.
Guest PC, et al. Proteomic profiling in schizophrenia: enabling stratification for more effective treatment. Genome Med. 2013 Mar 26;5(3):25. DOI: 10.1186/gm429. PMID: 23531373; PMCID: PMC3706977.