Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia

Abstract

Antipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2–3 episodes 110; 4–6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.

Higher stress response and altered quality of life in schizophrenia patients with low membrane levels of docosahexaenoic acid

“…Previous studies have shown that antipsychotics have variable effects on FA levels. Some studies found no effect (30, 37, 52) while 10.3389/fpsyt.2023.1089724 others observed little effect (31, 53) of AP treatment on FA levels, which seemed to depend on the type of AP (typical vs. atypical) used and/or the phase (acute vs. chronic) of the disease under investigation (54,55). In our case, because the sample size was too low, we could not make any correlation between PUFA levels and type of treatment or number of episodes.…”

Erythrocytes as Messengers for Information and Energy Exchange between Cells

“…The Erythrocyte -A Unique Cell in erythrocyte membranes of schizophrenia patients has given rise to a modified version of the dopamine hypothesis of schizophrenia [150]. A study of erythrocyte fatty acids in schizophrenia patients found that omega-3 polyunsaturated fatty acids were significantly lower and the omega-6:omega-3 fatty acid ratio was significantly higher in the group with dominantly negative symptoms as compared to the group with dominantly positive symptoms [151].…”

Peripheral biomarkers of treatment-resistant schizophrenia: Genetic, inflammation and stress perspectives

“…In addition, changes in C22:5n3 and omega 3 index, as well as gender and frequency of episodes, were all significant risk variables for diminished treatment response. Using a targeted metabolomics approach, the study revealed abnormalities in fatty acid metabolism that lead to a reduced response to treatment in patients with multiple schizophrenia ( Li et al, 2022 ).…”

“…Glyoxalase breaks down the RCO into lactic acid and glutathione for detoxification and the rate-limiting enzymes in this metabolic pathway are glyoxalase 1 and 2 (GLO1 and GLO2)( Kouidrat et al, 2015 ; Rodrigues et al, 2020 ). Besides, Pyridoxamine, one of the three forms of vitamin B6, can detoxify RCO, including AGEs ( Li et al, 2022 ). There is increasing evidence that carbonyl stress is closely associated with schizophrenia accompanied by exhibiting high plasma pentosidine and low serum vitamin B6 levels ( Miyashita et al, 2014 ).…”

“…TRS may be a subtype of schizophrenia with distinct neurological foundations, based on the mounting results of antipsychotic responsiveness and biomarkers. However, compared with a portion of patients who fail to respond to initial treatment, many patients develop TRS as the disease progressed, which may be caused by the aggravation of neurobiological impairment caused by recurrence or long-term untreated psychosis ( Takeuchi et al, 2019 ; Li et al, 2022 ). These two features cannot be disentangled according to the content of this review, the available data favors the combined effects of the two aspects.…”