Objective: Major depressive disorder (MDD) is a common and disabling illness associated with significant functional and psychosocial impairment. Currently, 60–70% of patients affected by MDD will ultimately respond to trials of standard medication; therefore, there are still nearly 30% of MDD patients who fail to respond satisfactorily to the available antidepressant treatments (Treatment Resistant Depression-TRD). The primary objective of this study is to compare pre-and post-treatment serum BDNF levels, illness severity and cognitive performance in patients with drug-resistant major depressive disorder (MDD) who received a complete cycle of repetitive transcranial magnetic stimulation (rTMS). Secondly, the correlation between serum BDNF level, illness severity and cognitive performance was assessed. We hypothesize rTMS will increase serum BDNF levels and will improve cognitive functions, inducing a neuro-protective effect, which contributes to decreased the global illness severity. A correlation between the change in BDNF levels and change in symptom severity may suggest that BDNF has a central role in the molecular mechanism of action of rTMS treatments. Furthermore, such a finding would support BDNF as a biochemical marker of MDD. Methods: This prospective, controlled study comparing pre-and post-treatment serum BDNF levels, illness severity and cognitive performance of 25 outpatients with drug-resistant MDD who received rTMS treatment (20 session-4weeks) in add-on to psychopharmacological treatment(N=13) or received only psychopharmacological treatment(N=12). Before starting the first stimulation session a blood sample for DNA extraction was taken from each subject. Serum BDNF levels were measured 1 week prior to (Baseline-B) and 1 week, after treatment (Endpoint-E), using the human BDNF ELISA kit. Depression severity was measured 1 week before and and 1 week after treatment, using the Hamilton Depression Rating Scale-21 item (HAM-D 21) and the Clinical Global Impression (CGI). Cognitive Performance was measured 1 week prior to and 1 week after treatment using Trail-Making Test (TMT), Digit Span Test (DST), Verbal Fluency Test, Mini Mental State Examination (MMSE). Results: All patients in the active group showed a significant HAM-D 21 and CGI score reduction, respectively from 22±3.67(B) to 10.31±5.60(E) (p=3.272e-06) and from 4,23±0,72(B) to 2,69±0,75(E) (p=1,889e-05) compared to the lack of therapeutic response in the patients who haven’t received rTMS. Full remission (HAM-D 21≤8) was achieved in 5of 13patients in the active group. The average of the scores obtained by the patients who received rTMS on the CGI-Improvement scale was 1.84±1.06, while the average of the scores obtained by the controls was 3.66± 0.98 (p=0.0001909). In patients treated with rTMS, cognitive performance improved. The patients in the active group showed a significant MMSE and Digit Span Test score increase, respectively from 25,36±2.60(B) to 28±2.08(E) (p= 0.009068) and from 9,53 ±4,19(B) to 13,15±4,01(p=0.03434) compared to the lack of therapeutic response in the patients who haven’t received rTMS. There was no significant difference in serum BDNF levels before and after rTMS. Post-treatment BDNF concentration was not significantly correlated with post-treatment depression severity or cognitive performance in patients who received rTMS. Conclusions: Our study suggests a clinically relevant response from rTMS over the left dorsolateral prefrontal cortex in patients with TRD. Active rTMS treatment was, moreover, associated with gains across the majority of domains of cognitive functioning examined. However rTMS may not exert their clinical effects by altering serum BDNF levels in patients with drug-resistant MDD. Serum BDNF concentration may not be a biomarker of rTMS treatment response. Further replications in larger samples will help to clarify the relevance of this preliminary data in the rTMS mechanism of action.
EFFETTI DELLA STIMOLAZIONE MAGNETICA TRANSCRANICA RIPETITIVA SU LIVELLI SIERICI DI BDNF, GRAVITA’ DI PATOLOGIA E PERFORMANCE COGNITIVA IN PAZIENTI ADULTI AFFETTI DA DISTURBO DEPRESSIVO MAGGIORE FARMACORESISTENTE
SANNA, LUCIA
2019-06-21
Abstract
Objective: Major depressive disorder (MDD) is a common and disabling illness associated with significant functional and psychosocial impairment. Currently, 60–70% of patients affected by MDD will ultimately respond to trials of standard medication; therefore, there are still nearly 30% of MDD patients who fail to respond satisfactorily to the available antidepressant treatments (Treatment Resistant Depression-TRD). The primary objective of this study is to compare pre-and post-treatment serum BDNF levels, illness severity and cognitive performance in patients with drug-resistant major depressive disorder (MDD) who received a complete cycle of repetitive transcranial magnetic stimulation (rTMS). Secondly, the correlation between serum BDNF level, illness severity and cognitive performance was assessed. We hypothesize rTMS will increase serum BDNF levels and will improve cognitive functions, inducing a neuro-protective effect, which contributes to decreased the global illness severity. A correlation between the change in BDNF levels and change in symptom severity may suggest that BDNF has a central role in the molecular mechanism of action of rTMS treatments. Furthermore, such a finding would support BDNF as a biochemical marker of MDD. Methods: This prospective, controlled study comparing pre-and post-treatment serum BDNF levels, illness severity and cognitive performance of 25 outpatients with drug-resistant MDD who received rTMS treatment (20 session-4weeks) in add-on to psychopharmacological treatment(N=13) or received only psychopharmacological treatment(N=12). Before starting the first stimulation session a blood sample for DNA extraction was taken from each subject. Serum BDNF levels were measured 1 week prior to (Baseline-B) and 1 week, after treatment (Endpoint-E), using the human BDNF ELISA kit. Depression severity was measured 1 week before and and 1 week after treatment, using the Hamilton Depression Rating Scale-21 item (HAM-D 21) and the Clinical Global Impression (CGI). Cognitive Performance was measured 1 week prior to and 1 week after treatment using Trail-Making Test (TMT), Digit Span Test (DST), Verbal Fluency Test, Mini Mental State Examination (MMSE). Results: All patients in the active group showed a significant HAM-D 21 and CGI score reduction, respectively from 22±3.67(B) to 10.31±5.60(E) (p=3.272e-06) and from 4,23±0,72(B) to 2,69±0,75(E) (p=1,889e-05) compared to the lack of therapeutic response in the patients who haven’t received rTMS. Full remission (HAM-D 21≤8) was achieved in 5of 13patients in the active group. The average of the scores obtained by the patients who received rTMS on the CGI-Improvement scale was 1.84±1.06, while the average of the scores obtained by the controls was 3.66± 0.98 (p=0.0001909). In patients treated with rTMS, cognitive performance improved. The patients in the active group showed a significant MMSE and Digit Span Test score increase, respectively from 25,36±2.60(B) to 28±2.08(E) (p= 0.009068) and from 9,53 ±4,19(B) to 13,15±4,01(p=0.03434) compared to the lack of therapeutic response in the patients who haven’t received rTMS. There was no significant difference in serum BDNF levels before and after rTMS. Post-treatment BDNF concentration was not significantly correlated with post-treatment depression severity or cognitive performance in patients who received rTMS. Conclusions: Our study suggests a clinically relevant response from rTMS over the left dorsolateral prefrontal cortex in patients with TRD. Active rTMS treatment was, moreover, associated with gains across the majority of domains of cognitive functioning examined. However rTMS may not exert their clinical effects by altering serum BDNF levels in patients with drug-resistant MDD. Serum BDNF concentration may not be a biomarker of rTMS treatment response. Further replications in larger samples will help to clarify the relevance of this preliminary data in the rTMS mechanism of action.
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