A Cochrane review included 7 studies. According to single studies, there was no evidence of the effectiveness of ceruletide, gamma-linolenic acid, oestrogen, lithium, phenylalanine, or insulin. Ceruletide was not clearly more effective than placebo (RR 0.82, CI 0.6 to 1.1; 2 RCTs, n=132). This also applied to gamma-linolenic acid, although data were sparse (RR 1.00, CI 0.7 to 1.5; 1 RCT, n=16), oestrogen (RR 1.2, CI 0.8 to 1.7; 1 RCT, n=12), and lithium (RR 1.39, CI 0.6 to 3.1; 1 RCT, n=11). Phenylalanine may even be detrimental (MD AIMS score 4.40, CI 1.16 to 7.64; 1 RCT, n=18). One small study (n=20) found that insulin was more likely to produce a clinical improvement in tardive dyskinesia than placebo (RR 0.5 CI 0.3 to 0.9, NNT 2 CI 1 to 5).
Comment: The quality of evidence is downgraded by study quality (inadequate or unclear allocation concealment) and by imprecise results (few patients and wide confidence intervals).
Another Cochrane review included 3 studies with 80 inpatients with schizophrenia. They were aged 18 to 71 years and followed up for a period 9 to 26 weeks. Overall, pyridoxal 5 phosphate (P5P) produced a significant improvement in tardive dyskinesia symptoms when compared with placebo, assessed by a change in Extrapyramidal Symptoms Rating Scale (ESRS) scores from baseline to the end of the first phase of the included studies (RR 19.97, CI 2.87 to 139.19; 2 RCTs, n = 65). The endpoint tardive dyskinesia score (a measure of its severity) assessed with the ESRS, was significantly lower among participants on P5P (MD -4.07, CI -6.36 to -1.79; 2 RCTs, n = 60). It was unclear whether P5P led to more side effects (RR 3.97, CI 0.20 to 78.59; 2 RCTs, n = 65) or caused deterioration in tardive dyskinesia symptoms when compared to placebo (RR 0.16, CI 0.01 to 3.14; 2 RCTs, n = 65). Five patients on P5P and none on placebo withdrew from the study because they were not willing to take more medications (RR 8.72, CI 0.51 to 149.75; 2 RCTs, n = 65). There was no significant difference in the endpoint positive and negative psychiatric symptoms scores, measured using the Positive and Negative symptoms Scale (PANSS) between participants taking P5P and those taking placebo. For the positive symptoms: (MD -1.50, CI -4.80 to 1.80; 1 RCT, n = 15). For the negative symptoms: (MD -1.10, CI -5.92 to 3.72; n = 15, 1 RCT).
Comment: The quality of evidence is downgraded by indirectness (short follow-up time) and by imprecise results (few patients and wide confidence intervals).