Biomarkers Linked to L-Methylfolate Effectiveness for Depression

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.

PHOENIX  – L-Methylfolate represents an effective and well-tolerated adjunctive therapy for patients with major depressive disorder who fail to respond adequately to treatment with selective serotonin reuptake inhibitors – particularly those patients with certain biomarkers and genotypes associated with metabolic dysfunction.

The folate derivative, which is categorized as a trimonoamine modulator, was shown in a 2011 double-blind, placebo-controlled, parallel-sequential study of 75 patients with SSRI-resistant major depressive disorder to be superior to placebo as an adjunctive therapy when given at a dose of 15 mg/day.

In that study, the pooled difference in response rates on the 17-item Hamilton Depression Rating Scale (HDRS-17) after 30 days between patients who received adjunctive L-methylfolate and those who received SSRI therapy plus placebo was 17.7%, Dr. George I. Papakostas, one of the study authors, said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The pooled differences in mean change on the HDRS-17 and HDRS-28 also differed significantly between the groups, indicating greater improvement in depressive symptoms in the L-methylfolate group, he reported.

Greater improvement also was demonstrated on secondary outcome measures, including changes in scores on the patient-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S), in those who received L-methylfolate, said Dr. Papakostas of Massachusetts General Hospital, Boston.

In a new analysis looking at secondary genomic and biomarker end points and their association with treatment effect, it was noted that effects were similar in patients with baseline L-methylfolate levels below and above the median. However, a greater treatment effect was observed in patients with an allelic variant in the methylenetetrahydrofolate reductase (MTHFR) C677T genotype. There was a difference in mean change in HDRS-28 of –3.75 for those with the "t" allele, compared with –1.99 for the "cc" allele, Dr. Papakostas reported.

Furthermore, patients with a body mass index of 30 kg/m² or greater also experienced a significantly greater reduction in depressive symptoms following treatment with L-methylfolate – a difference in mean change in HDRS-28 of –4.66.

Study participants were outpatients who had no response, or only a partial response, to SSRIs. The 60-day multicenter trial used a novel sequential parallel comparison design, and was thus divided into two 30-day phases. In addition to their SSRI treatment, patients were randomized to receive either adjunctive L-methylfolate for 60 days, placebo for 30 days followed by L-methylfolate for 30 days, or placebo for 60 days.

The findings suggest that biomarkers could play a role in individualizing L-methylfolate therapy in depressed patients, Dr. Papakostas said.

Findings from another post hoc analysis of the data, which were presented in a poster at the meeting by Dr. Papakostas and Dr. Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, Calif., suggest that L-methylfolate improves outcomes by addressing metabolic imbalances associated with elevated BMI, as well as with inflammation.

BMI and inflammatory markers such as C-reactive protein have been shown to be independently associated with MDD, and increased body weight is associated with decreased response to antidepressants, the authors noted.

For this analysis, they assessed the effect of L-methylfolate as an adjunct to SSRI treatment on the Maier subscale of the HDRS and correlations with inflammatory biomarkers.

The mean change on the Maier subscale was –3.3 for patients who received L-methylfolate, compared with –1.5 for those who received placebo, based on pooled data. The mean improvement in symptoms also was significantly greater in the L-methylfolate patients versus the placebo patients when BMI was 30 kg/m² or greater (–7.4 vs. –2.4, respectively), and when elevated baseline high-sensitivity C-reactive protein (hsCRP) was above the median of 2.25 mg/L (–7.7 vs. –3.7, respectively). Other biomarkers for which significant associations were seen included S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) less than 2.71 and 4-hydroxynonenal (4-HNE) of 3.28 mcg/mL or greater.

Stratification by genotype showed that the pooled mean change from baseline with L-methylfolate vs. placebo was significantly greater in patients with the 5-methyltetrahydrofolate methyltransferase (MTR) 2756 AG/GG or the MTR reductase (MTRR) 66 AG/GG genotype, the investigators said, noting that a trend toward significance was seen for the MTHFR 677CT/TT genotype.

"Improvement in core symptoms on the Maier subscale was significantly correlated with BMI of 30 kg/m² or greater, 4-HNE greater than the study median, SAM/SAH ratio less than the study median, and hsCRP less than the study median. Changes in core symptoms on the Maier subscale also were significantly associated with the MTR 2756 AG/GG genotype," they wrote in the poster.

"Effects on biomarkers of metabolic dysregulation may explain the significant impact of L-methylfolate on core symptoms of depression in patients with SSRI-resistant MDD," the investigators concluded.

The findings represent a "consistent signal suggesting that something is going on with respect to the metabolic, inflammatory, and oxidative profile of some patients that renders them ... particularly susceptible to the therapeutic effects of L-methylfolate as adjunctive therapy above and beyond placebo," Dr. Papakostas said, stressing that confirmatory trials are needed.

These studies were supported by a grant from PamLab. Dr. Papakostas and Dr. Stahl disclosed financial relationships with numerous pharmaceutical companies.