Effect of add-on alpha lipoic acid on psychopathology in patients with treatment-resistant schizophrenia: a pilot randomized double-blind placebo-controlled trial

Abstract

Rationale Alpha lipoic acid is known to reverse NMDA receptor hypofunction in addition to dopamine receptor blockade activity. It also enhances neurotrophic factors and has antioxidant potential. These properties combined together may be beneficial for treatment-resistant schizophrenia (TRS). Objectives This study evaluates the effect of alpha lipoic acid (ALA) on psychopathological scores (positive, negative, cognitive), neurotrophic factors and oxidative stress in TRS. Methods A pilot randomized double-blind placebo-controlled parallel design trial was conducted in 20 patients with TRS. After initial screening, participants were randomized into test (add-on ALA) and control (add-on placebo) groups. After recruitment, clinical evaluations with scale for assessment of positive symptoms and negative symptoms (SAPS and SANS), schizophrenia cognitive rating scale (SCoRS), UKU side effect rating scale were done. Serum levels of BDNF, MDA, and GSH were estimated. Patients were followed up for 8 weeks, and clinical and biochemical evaluations were repeated. Adherence to medication was evaluated at follow-up. Results A significantly greater improvement was found in SANS score in the test group when compared to control (Mann–Whitney U = 17.0; p = 0.021), whereas there was no significant improvement in SAPS score (Mann–Whitney U = 41.5; p = 0.780). A significant increase in BDNF levels was observed in the control group when compared to ALA ( U = 20.0; p = 0.041). No significant differences were found between the test and control groups in serum MDA ( U = 30.0; p = 0.221), serum GSH ( U = 40.0; p = 0.683), and medication adherence rating scale (MARS) scores ( U = 44.0; p = 0.934). Conclusions ALA supplementation improved psychopathology and decreased oxidative stress in patients with TRS. This study thus shows the potential of adjunctive ALA in TRS. Trial registration The study was prospectively registered in Clinical Trial Registry of India (CTRI/2020/03/023707 dated 02.03.2020).

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

“…However, clozapine showed inhibitory effects on dopaminergic activity in the midbrain [ 126 ], mediated by its action on the glycine binding site located on the NMDAR [ 127 ], mitigating the symptom dimension in schizophrenia [ 126 ]. Alpha lipoic acid (ALA) has been held responsible for reversing NMDAR hypofunction, as well as blocking dopamine receptors and increasing neurotrophic factors with an antioxidant effect [ 128 ]. Its potential use in TRS has been assessed in a randomized clinical trial (RCT) study that found a significantly greater improvement in the test group compared with the control in the Scale for the Assessment of Negative Symptoms (SANS) scores.…”

“…Its potential use in TRS has been assessed in a randomized clinical trial (RCT) study that found a significantly greater improvement in the test group compared with the control in the Scale for the Assessment of Negative Symptoms (SANS) scores. ALA supplementation improved psychopathology and decreased oxidative stress in patients with TRS [ 128 ]. In contrast, another RCT in patients with schizophrenia under supplementation with ALA found no significant improvement in body mass index, cognition, psychopathology, adverse effects of antipsychotics or oxidative stress, and inflammation in the experimental group compared to placebo.…”

Alpha Lipoic Acid for Schizophrenia

“…1 Treatment with alpha lipoic acid (ALA), a dihydrolipoic acid with antioxidant, antiinflammatory, and neuroprotective properties, may restore oxidative stress-induced brain damage. [2][3][4][5] To test this hypothesis, De Lima et al 2 conducted a 16-week, double-blind, placebo-controlled trial of ALA among individuals with schizophrenia who were also taking antipsychotics. However, their study showed that ALA did not have any effects on the psychopathology of individuals with schizophrenia.…”

“…6 To date, 4 double-blind, randomized, placebo-controlled trials of ALA for individuals with schizophrenia have been published (Supplemental Table S1, http:// links.lww.com/JCP/A853). [2][3][4][5] To assess the efficacy and acceptability of ALA in the treatment of schizophrenia, we conducted a systematic review and meta-analysis of these studies.…”

“…lww.com/JCP/A853). [2][3][4][5] The study characteristics are presented in Supplemental Table S1, http://links.lww.com/JCP/A853, and the risk of bias is shown in Figure S2. The mean age of the participants was 35.52 years, and 36.41% of them were men.…”