Schizophrenia is a severe mental health condition which affects approximately 24 million people worldwide (World Health Organisation, 2022). Though its presentation can vary from one person to another, it typically includes symptoms of delusions and hallucinations, alongside emotional dysfunction, impaired social functioning, and thinking difficulties (American Psychiatric Association, 2013).

Antipsychotic medications are the primary treatment approaches, however, an estimated one-third of people living with schizophrenia are reported to have ‘treatment-resistant schizophrenia’ (Diniz et al., 2023; Chan et al., 2021). Treatment-resistant schizophrenia (TRS) is generally understood as a failure to respond to at least two trials of antipsychotic medication administered at an adequate dose and duration (Polese et al., 2019). Often, antipsychotics are prescribed as optimal treatments, but people can experience unwanted treatment side-effects such as weight gain (Dong et al., 2024).

Discussions of non-medication-based interventions for TRS, including psychological and psychosocial interventions, have received comparatively less attention. When they are provided, psychological and psychosocial interventions are typically offered alongside medication. While there are several efficacious psychological interventions in psychosis, such as cognitive behavioural therapy and family interventions (National Institute for Health and Care Excellence, 2014), it would be helpful to understand more about their efficacy, acceptability, and tolerability in individuals with TRS.

Salahuddin et al. (2024) sought to address this issue by conducting a systematic review and the first network meta-analysis of psychological and psychosocial interventions for TRS. This blog reviews their findings with consideration of wider implications.

Methods

In their systematic review, Salahuddin et al. (2024) searched 11 databases and registries for published and unpublished randomised controlled trials (RCTs). Studies were included if they compared psychological and psychosocial interventions with treatment as usual, waiting-list controls, or inactive controls. Participants in the included studies were described as treatment-resistant based on the definition given by the respective authors. There were no restrictions on publication date, country, setting, language, ethnicity, or gender.  Studies were excluded if they included participants with psychiatric comorbidities. The primary outcome measured was the overall symptoms of schizophrenia.

A network meta-analysis was then performed to compare the effectiveness of various psychological and psychosocial interventions. Additionally, a random-effects pairwise meta-analysis was conducted to evaluate outcomes, including overall symptoms, quality of life, and treatment adverse events.

Results

The database searches identified 30,326 records. Following title and abstract screening, 5,762 full texts were screened for eligibility. The included studies had a sample size of 5,034 participants with TRS and integrated data from 52 studies, which assessed 20 different psychological and psychosocial interventions.

For the network meta-analysis, 31 studies with 12 interventions were analysed to determine the outcome of overall symptoms. For each intervention type, the standardised mean difference was measured between the intervention and treatment as usual.

• The network meta-analysis identified music therapy as having the biggest effect size for reducing overall symptoms of TRS. It resulted in a standardised mean difference (SMD) of –1.27 (95% CI –1.83 to –0.70), but this was based on a single trial involving 41 participants (Yang et al., 1998), so these findings are not reliable.
• Integrated interventions (i.e., a combination of multiple treatments) and virtual reality interventions were effective, with SMDs of –0.70 (95% CI –1.18 to –0.22) and –0.41 (95% CI –0.79 to –0.02), based on three and four trials, respectively.
• Cognitive Behavioural Therapy for Psychosis (CBTp) had a smaller effect size (SMD –0.22, 95% CI –0.35 to –0.09) but was supported by the largest body of evidence, with 1,835 participants involved in these combined trials. However, no CBTp studies using a stringent definition of treatment resistance were available. Additionally, in eight TRS studies where at least two antipsychotics had been trialled and were ineffective, no clear differences between CBTp and treatment as usual were observed (SMD –0.16, 95% CI –0.54 to 0.23).

Sensitivity analysis was conducted to assess the robustness of findings, and subgroup analysis was conducted to assess the stringency of the TRS criterion as a moderator. Results from both the subgroup and sensitivity analyses showed congruent results with the main analysis, whereby CBTp, integrated interventions, and virtual reality therapy were effective when compared to treatment as usual.

• Family intervention, metacognitive training, integrated interventions, virtual reality intervention, and CBTp may help with the positive symptoms of schizophrenia.
• In contrast, CBTp, music therapy, occupational therapy, and body-oriented intervention may help with negative symptoms.

In terms of acceptability, for most interventions there were higher numbers of participant dropouts when compared to treatment as usual. Studies provided limited data on adverse events related to the psychological interventions, so analysis was not possible.

Conclusions

Salahuddin and colleagues (2024) suggest that CBTp should be prioritised as an add-on treatment to medication for people with TRS. Among the interventions studied, CBTp was the sole intervention supported by data from a large body of studies with several participants. In addition to improving overall symptoms, participants in these studies also reported a better quality of life.

The Salahuddin et al. (2024) network meta-analysis also shows that CBTp had an impact on positive symptoms (i.e., hallucinations and delusions), but was less effective for negative symptoms such as lack of motivation or pleasure.

While CBTp stands out as an effective option, other types of interventions such as virtual reality therapy and integrated approaches show promise. However, the quantity of studies and data are not sufficient to draw strong conclusions at this stage.

Strengths and limitations

Salahuddin et al.’s (2024) study is the first network meta-analysis to provide a comprehensive picture of research to date demonstrating the efficacy, acceptability, and tolerability of psychosocial and psychological interventions for people with schizophrenia whose symptoms are defined as ‘treatment resistant’. The use of a network meta-analysis provides a robust methodology, allowing for the comparison of interventions simultaneously, even when direct head-to-head comparisons are not available.

While there are clear strengths from the present study, limitations are also evident. One relates to the lack of a standardised definition of ‘treatment-resistant schizophrenia (TRS)’ across the included studies. This can cause heterogeneity within the data, affecting the generalisability of findings. The generalisability of findings was also affected by the limited data on therapies other than CBTp. Several interventions were supported by only a small number of studies or even just one. For example, the findings on music therapy, though promising, come from a single small study of 41 participants.

Notably, potential adverse and harmful effects of intervention types and dropout rates were not identified in this network meta-analysis. This is an important omission for several reasons. For example, higher dropout rates in psychological interventions when compared to treatment as usual might suggest that these therapies might be difficult for some people to engage with, which could limit their real-world applicability. As discussions around iatrogenic harm and the potential dangers of psychological therapies come to the forefront (Parry et al., 2016), it is also critical that the potential risks of psychological interventions are reported in research.

Ethnicity data in the included studies was limited. Thus, it is difficult to determine whether intervention effects are similar across different ethnic groups. This is especially salient as some racially minoritised groups, for example those from Black ethnic minority backgrounds, are disproportionately diagnosed with schizophrenia at higher rates in some areas across the globe (Anglin et al., 2023). As a result, the study’s findings may not accurately reflect the experiences or outcomes for these populations.

Finally, this study did not factor in people with lived experience of TRS, whose perspectives could have added a rich layer of understanding about how these therapies are perceived and what practical challenges come with them. Engaging people with lived experience in psychiatric research is essential to avoid power discrepancies and missing narratives (Hawke et al., 2022). Without their involvement, valuable insights are lost, and knowledge exchange is limited. Including people with lived experience in all stages of research – from conception to delivery – not only enhances knowledge-sharing but is also central to stigma reduction (Thornicroft et al., 2022).

Implications for practice

Salahuddin et al.’s (2024) review highlights the potential of emerging interventions like virtual reality therapy and integrated interventions. Accordingly, a recent review by Imogen Bell et al. (2024) suggests that virtual reality-based treatments can effectively address psychosis symptoms such as paranoia and auditory hallucinations, and individuals with lived experience of psychosis report positive attitudes towards using a virtual environment. While the evidence is not as established for these therapies as it is for CBTp, they are still worth considering.

Clinicians might also need to combine therapies to tackle the full spectrum of schizophrenia symptoms and their impacts. This opens the door for future research into therapies specifically targeting negative symptoms, which have been identified as vital treatment targets for improving functioning (i.e., daily living activities such as self-care, social participation, and employment; Bighelli et al., 2022) in individuals with TRS (Li et al., 2024). For example, Staring et al. (2013) found that cognitive behavioural therapy for negative symptoms seemed to be effective in reducing negative symptoms in a study involving 21 adult outpatients with schizophrenia spectrum disorders. Additionally, a review by Muyambi et al. (2023) indicated that behavioural activation could enhance motivation and mood in adults with negative symptoms by encouraging engagement in meaningful activities. However, it is important to note that there were only two studies included in Muyambi et al.’s (2023) review, and both had small sample sizes and were defined as being of low quality on a quality appraisal measure (Choi et al., 2016; Mairs et al., 2011), thus underscoring the need for further research in this area.

The implementation of psychological interventions, such as CBTp, is likely to come with a range of challenges. For example, in the UK, among these challenges is the fact the proportion of the NHS England budget spent on mental health has decreased since 2016/17 (British Medical Association, 2024). A systematic review by Burgess-Barr et al. (2023) also found that access to recommended psychological therapies for psychosis remains low across Europe, North America, and Australia, with organisational, staff, and service user barriers. As a result, resources and capacity in many mental health services are limited. In addition, there are stark inequities in accessing psychological therapy among marginalised groups worldwide. For instance, in low- and middle-income countries, a severe shortage of mental health specialists means that 69% of people with schizophrenia in these countries cannot access evidence-based care, a disparity known as the ‘treatment gap’ (Lora et al., 2012). Critical consideration of these limitations is essential prior to implementation.

Overall, this review provides insight into what approaches might be helpful in supporting the not insignificant number of people living with TRS. However, it also shows that there is still much to explore and refine. There is a continued need to establish robust evidence-based interventions for people living with TRS.

Authorship

This work represents equal contribution from Kalya Aung, Angela Kibia, and Dorothy Williams (contributors represented alphabetically), supported by Dr Juliana Onwumere.

Statement of interests

We have no conflicting interests connected to the study.

Links

Primary paper

Salahuddin, N. H., Schütz, A., Pitschel-Walz, G., Mayer, S. F., Chaimani, A., Siafis, S., Priller, J., Leucht, S., & Bighelli, I. (2024). Psychological and psychosocial interventions for treatment-resistant schizophrenia: a systematic review and network meta-analysis. The Lancet Psychiatry, 11(7), 545-553. https://doi.org/10.1016/S2215-0366(24)00136-6

Other references

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596

Anglin DM, Lui F. Racial microaggressions and major discriminatory events explain ethnoracial differences in psychotic experiences. Schizophrenia Research. 2023 Mar 1;253:5-13.

Bell, I. H., Pot-Kolder, R., Rizzo, A., Rus-Calafell, M., Cardi, V., Cella, M., Ward, T., Riches, S., Reinoso, M., Thompson, A., Alvarez-Jimenez, M., & Valmaggia, L. (2024). Advances in the use of virtual reality to treat mental health conditions. Nature Reviews Psychology, 3(8), 552-567. https://doi.org/10.1038/s44159-024-00334-9

Bighelli, I., Wallis, S., Reitmeir, C., Schwermann, F., Salahuddin, N. H., & Leucht, S. (2022). Effects of psychological treatments on functioning in people with Schizophrenia: a systematic review and meta-analysis of randomized controlled trials. European Archives of Psychiatry and Clinical Neuroscience, 273(4), 779-810. https://doi.org/10.1007/s00406-022-01526-1

British Medical Association. (2024, October 4). Mental health pressures data analysis. The British Medical Association. https://www.bma.org.uk/advice-and-support/nhs-delivery-and-workforce/pressures/mental-health-pressures-data-analysis

Burgess-Barr, S., Nicholas, E., Venus, B., Singh, N., Nethercott, A., Taylor, G., & Jacobsen, P. (2023). International rates of receipt of psychological therapy for psychosis and schizophrenia: systematic review and meta-analysis. International Journal of Mental Health Systems, 17(1), 8. https://doi.org/10.1186/s13033-023-00576-9

Chan, S. K. W., Chan, H. Y. V., Honer, W. G., Bastiampillai, T., Suen, Y. N., Yeung, W. S., Lam, M., Lee, W. K., Ng, R. M. K., Hui, C. L. M., Chang, W. C., Lee, E. H. M., & Chen, E. Y. H. (2020). Predictors of Treatment-Resistant and Clozapine-Resistant schizophrenia: A 12-Year follow-up study of First-Episode Schizophrenia-Spectrum disorders. Schizophrenia Bulletin, 47(2), 485-494. https://doi.org/10.1093/schbul/sbaa145

Choi, K. H., Jaekal, E., & Lee, G. Y. (2016). Motivational and Behavioral Activation as an Adjunct to Psychiatric Rehabilitation for Mild to Moderate Negative Symptoms in Individuals with Schizophrenia: A Proof-of-Concept Pilot Study. Frontiers in psychology, 7, 1759. https://doi.org/10.3389/fpsyg.2016.01759

Diniz, E., Fonseca, L., Rocha, D., Trevizol, A., Cerqueira, R., Ortiz, B., Brunoni, A. R., Bressan, R., Correll, C. U., & Gadelha, A. (2023). Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 45(5), 448–458. https://doi.org/10.47626/1516-4446-2023-3126

Dong, S., Schneider-Thoma, J., Bighelli, I., Siafis, S., Wang, D., Burschinski, A., Schestag, K., Samara, M., & Leucht, S. (2023). A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia. European Archives of Psychiatry and Clinical Neuroscience. https://doi.org/10.1007/s00406-023-01654-2

Hawke, L. D., Sheikhan, N. Y., Jones, N., Slade, M., Soklaridis, S., Wells, S., & Castle, D. (2022). Embedding lived experience into mental health academic research organizations: critical reflections. Health Expectations, 25(5), 2299-2305. https://doi.org/10.1111/hex.13586

Li, Y., Ang, M. S., Yee, J. Y., See, Y. M., & Lee, J. (2024). Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition. Frontiers in Psychiatry, 15, 1444843. https://doi.org/10.3389/fpsyt.2024.1444843

Lora, A., Kohn, R., Levav, I., McBain, R., Morris, J., & Saxena, S. (2012). Service availability and utilization and treatment gap for schizophrenic disorders: a survey in 50 low- and middle-income countries. Bulletin of the World Health Organization, 90(1), 47–54B. https://doi.org/10.2471/BLT.11.089284

Mairs, H., Lovell, K., Campbell, M., & Keeley, P. (2011). Development and Pilot Investigation of Behavioral Activation for Negative Symptoms. Behavior Modification, 35(5), 486-506. https://doi.org/10.1177/0145445511411706

Muyambi, K., Walsh, S., Bressington, D., Gray, R., Dennis, S., Brown, E., Grimshaw, M., Drummond, J., & Jones, M. (2023). Efficacy of behavioural activation in the treatment of negative symptoms in people with schizophrenia spectrum disorders: A systematic review. International journal of nursing studies advances, 5, 100132. https://doi.org/10.1016/j.ijnsa.2023.100132

National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. (Clinical guideline 178.) 2014. https://www.nice.org.uk/guidance/cg178

Parry, G. D., Crawford, M. J., & Duggan, C. (2016). Iatrogenic harm from psychological therapies – time to move on. British Journal of Psychiatry, 208(3), 210–212. https://doi.org/10.1192/bjp.bp.115.163618

Polese, D., Fornaro, M., Palermo, M., De Luca, V., & de Bartolomeis, A. (2019). Treatment-Resistant to Antipsychotics: A Resistance to Everything? Psychotherapy in Treatment-Resistant Schizophrenia and Nonaffective Psychosis: A 25-Year Systematic Review and Exploratory Meta-Analysis. Frontiers in Psychiatry, 10, 210. https://doi.org/10.3389/fpsyt.2019.00210

Staring, A. B., Ter Huurne, M. A. B., & van der Gaag, M. (2013). Cognitive Behavioral Therapy for negative symptoms (CBT-n) in psychotic disorders: a pilot study. Journal of Behavior Therapy and Experimental Psychiatry, 44(3), 300-306. https://doi.org/10.1016/j.jbtep.2013.01.004

Thornicroft, G., Sunkel, C., Alikhon Aliev, A., Baker, S., Brohan, E., El Chammay, R., Davies, K., Demissie, M., Duncan, J., Fekadu, W., Gronholm, P. C., Guerrero, Z., Gurung, D., Habtamu, K., Hanlon, C., Heim, E., Henderson, C., Hijazi, Z., Hoffman, C., Hosny, N., … Winkler, P. (2022). The Lancet Commission on ending stigma and discrimination in mental health. Lancet (London, England), 400(10361), 1438–1480. https://doi.org/10.1016/S0140-6736(22)01470-2 World Health Organization. (2022, January 10). Schizophrenia. World Health Organization; World Health Organization. https://www.who.int/news-room/fact-sheets/detail/schizophrenia

Yang, W. Y., Zheng, L., Yong Zhen, W., Zhang, H., Y., Bio, M. (1998). Psychosocial rehabilitation effects of music therapy in chronic schizophrenia. Hong Kong Journal of Psychiatry, 8(1), 38.

Photo credits

• Photo by Kyrie kim on Unsplash
• Photo by Marius Masalar on Unsplash