Understanding the baseline cognitive impairments in first-episode psychosis (FEP) prior to pharmacological intervention offers critical insights into the intrinsic nature of psychosis (Suvisaari et al., 2018).

Recent studies have been increasingly focusing on the cognitive deficits observed in patients with FEP (e.g., Morales-Muñoz et al., 2017). These impairments are recognised as potential early indicators of the disease’s progression and predictors of functional outcomes (Cuesta et al., 2024).

The current study (Lee et al., 2024) reviews over 50 studies with more than 5,500 participants to determine the extent of cognitive impairments in these patients across various cognitive domains such as processing speed, memory, and executive functioning.

The following research questions were investigated:

1. How much cognitive impairment do antipsychotic drug-naive FEP patients exhibit compared to healthy controls?
2. What is the degree of variability in cognitive functioning within the FEP patient group, and how does it compare to healthy controls?
3. How does the heterogeneity of study methodologies and samples affect the meta-analytical results on cognitive impairments in FEP?

Methods

The meta-analysis followed the PRISMA (Page et al., 2021) and MOOSE guidelines (Brooke et al., 2021).

The following search terms were used: ((((cognition OR cognitive OR neurocognitive OR neuropsychological OR neuropsychologic OR neurocognition)) AND ((psychosis OR psychotic OR schizophrenia))) AND ((drug naïve OR drug-naïve OR never treated OR never-treated OR neuroleptic naïve OR neuroleptic-naïve OR anti- psychotic naïve OR antipsychotic-naïve OR never medicated OR never- medicated OR treatment naïve OR treatment-naïve))) AND ((“2012″[Date – Publication]: “3000”[Date – Publication]), and the last search was performed on September 15th 2022.

Inclusion Criteria

• Primary studies involving antipsychotic drug–naive individuals diagnosed with first-episode psychosis.
• Cognitive function assessed as a primary outcome measure grouped into 7 domains (processing speed, attention, working memory, verbal learning, visual learning, reasoning, problem-solving, and executive function).
• Studies published in peer-reviewed journals.
• Studies providing sufficient data on the Duration of Untreated Psychosis (DUP)
• Comparison data from a healthy control group.

Exclusion Criteria

• Studies including individuals who had received antipsychotic treatment before the study commenced.
• Studies with insufficient or unclear reporting of cognitive outcomes.
• Studies that did not specify or limit the DUP.

To minimise confounding effects related to cognitive impairment associated with a prolonged period of untreated psychosis, the DUP was specifically limited in the included studies. This focus on very early psychosis aimed to ensure that the cognitive impairments analysed were less likely to be influenced by extended untreated psychosis, thereby providing a clearer assessment of cognitive function at the onset of the disorder.

Researchers extracted cognitive performance and demographic data separately from each study and resolved any inconsistencies. The study with the largest sample size was chosen for inclusion in cases of overlapping samples and cognitive tests.

The Hedges g was used to estimate the standardised mean differences between individuals with first-episode psychosis (FEP) and control groups across various cognitive domains. Additionally, the coefficient of variation ratios (CVRs) was used to assess the variability within each group.

Results

Sample

The initial search included 523 records from databases, registers, and other sources (e.g., citation searching). The study included a total of 50 studies comprising 2,625 patients with first-episode psychosis (FEP) and 2,917 healthy controls. The mean age of FEP patients was 25.2 years (SD = 3.6), with a 60% male demographic, and the mean age of controls was 26.0 years (SD = 4.6), with a 55% male demographic.

Cognitive Functioning in Antipsychotic Drug-Naïve Patients with FEP as Compared with Controls

Antipsychotic drug-naïve patients with first-episode psychosis (FEP) displayed significant cognitive impairment across all measured domains compared to controls. The largest effect sizes were observed in:

• speed of processing (−1.16; 95% CI, −1.35 to −0.98)
• verbal learning (−1.08; 95% CI, −1.28 to −0.88)
• visual learning (−1.05; 95% CI, −1.27 to −0.82)
• working memory (−1.04; 95% CI, −1.35 to −0.73)
• attention (−1.03; 95% CI, −1.24 to −0.82)
• reasoning/problem-solving (−0.90; 95% CI, −1.12 to −0.68)
• executive function (−0.88; 95% CI, −1.07 to −0.69).

Note: The larger the effect size the stronger the relationship between the two variables.

Heterogeneity, Study Quality, Publication Bias, and Meta-regression

The analysis revealed substantial heterogeneity in effect sizes across studies, with τ² values over 70%, indicating that observed variance was mostly due to differences in actual effects rather than sampling errors. The study quality varied with a mean quality rating of 6.1. No significant effects were found for potential moderators such as age, sex, education, publication year, and study quality in the meta-regression analysis.

Variability of Cognitive Functioning in Antipsychotic Drug-Naïve Patients with FEP as Compared with Controls

Patients with FEP showed greater within-group variability in cognitive performance compared to controls.

The coefficient of variation ratios (CVRs) indicated that the variability in patients was substantially higher, with CVR values ranging from 1.34 to 1.92 across cognitive domains.

Conclusions

The study has demonstrated that patients with first-episode psychosis who have not been treated with antipsychotic drugs exhibit significant cognitive impairments in different areas when compared to healthy individuals.

Strengths and limitations

This study has several strengths, including a large sample size and a thorough assessment of multiple cognitive domains, providing a detailed evaluation of cognitive impairments among antipsychotic drug-naïve patients experiencing their first episode of psychosis. Moreover, the inclusion of participants from diverse geographic locations (e.g., Turkey, Canada, Mexico, England, Denmark, China, South Africa, Spain) and a wide range of ages increases the generalisability of the results.

The studies included in the review were highly heterogeneous.  This suggests we should be cautious in our interpretation of the aggregated estimates. The lack of significant findings in meta-regression analyses for potential moderators such as age, sex, and education might indicate insufficient subgroup data or unmeasured confounding variables. Moreover, the study did not collect data on race and ethnicity, as the authors did not consider it a part of the research question.

The authors raised concerns in relation to cognitive testing in actively psychotic patients as this potentially could be affected by factors such as sleep deprivation, poor motivation and the active psychosis itself. Measured impairments  may not be directly due to psychosis.

The review addressed a well-defined question and utilised a thorough search strategy.. Important limitations include potential publication bias due to the exclusion of non-English studies and selection bias and availability bias stemming from the exclusion criteria.

In summary, high heterogeneity among the included studies, despite being managed with a random-effects model, could affect the precision and generalisability of the results. The researchers did not fully discuss the implications of this heterogeneity or the precision of their findings, particularly concerning wide confidence intervals. Additionally, while the study effectively assessed the validity of individual studies, the potential impact of unmeasured confounding variables and measurement biases, particularly in actively psychotic patients, suggests that the results should be interpreted cautiously.

Implications for practice

Incorporating systematic cognitive testing early in the diagnostic process can greatly benefit patients by identifying specific cognitive deficits that may influence both the choice of initial treatment strategies and long-term management plans. Within the NHS England framework, mental health professionals could use these data to tailor interventions that specifically target the cognitive areas most affected by early psychosis, such as processing speed, verbal learning, and working memory. For instance, early cognitive assessments could help determine the need for personalised cognitive behavioural therapy (CBT) or targeted cognitive training exercises, enhancing the efficacy of these interventions.

From a policy standpoint, these findings advocate for the integration of cognitive assessments into the standard care protocols for FEP. Healthcare systems should allocate resources to train clinicians in cognitive evaluation techniques and interpretation of results. Moreover, policies should support the establishment of specialized services or roles focused on cognitive assessment and rehabilitation within mental health care settings. Funding should also be directed towards cognitive support programs as a mandatory component of FEP care, ensuring these interventions are accessible and affordable for all affected individuals.

Finally, exploring how these cognitive impairments evolve over time without the influence of antipsychotic drugs could provide deeper insights into the natural progression of FEP and guide the development of phase-specific interventions. Future research into the efficacy of cognitive rehabilitation programs tailored to the needs of FEP patients could inform more effective treatment models, potentially altering disease outcomes.

The implementation of these changes in practice and policy based on the study’s findings could enhance the precision and effectiveness of early psychosis interventions.

Statement of interests

No conflicts of interest to declare.

Links

Primary paper

Lee, M., Cernvall, M., Borg, J., Plavén-Sigray, P., Larsson, C., Erhardt, S., … & Cervenka, S. (2024). Cognitive Function and Variability in Antipsychotic Drug–Naive Patients With First-Episode Psychosis: A Systematic Review and Meta-Analysis. JAMA Psychiatry.

Other references

Brooke, B. S., Schwartz, T. A., & Pawlik, T. M. (2021). MOOSE reporting guidelines for meta-analyses of observational studies. JAMA surgery, 156(8), 787-788.

Cuesta, M. J., Sánchez-Torres, A. M., Moreno-Izco, L., de Jalón, E. G., Gil-Berrozpe, G. J., Peralta, V., … & Rosado, E. (2024). Long-term trajectories of clinical staging in first-episode psychosis and their associated cognitive outcome: A 21-year follow-up study. Spanish Journal of Psychiatry and Mental Health.

Morales-Muñoz, I., Jurado-Barba, R., Fernández-Guinea, S., Álvarez-Alonso, M. J., Rodríguez-Jiménez, R., Jiménez-Arriero, M. A., & Rubio, G. (2017). Cognitive impairments in patients with first episode psychosis: The relationship between neurophysiological and neuropsychological assessments. Journal of Clinical Neuroscience, 36, 80-87.

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., … & Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj, 372.

Suvisaari, J., Mantere, O., Keinänen, J., Mäntylä, T., Rikandi, E., Lindgren, M., … & Raij, T. T. (2018). Is it possible to predict the future in first-episode psychosis?. Frontiers in psychiatry, 9, 580.

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