Vagus Nerve Stimulation for Resistant Mood Disorders
Vagus Nerve Stimulation for Resistant Mood Disorders
One hundred-fifty-nine subjects were interviewed through telephone in order to assess eligibility criteria for inclusion into the study; of them, 39 were asked to present for a face-to-face clinical interview. Thirty-three patients were excluded because of not having a current Major Depressive Episode (N = 7), not having a chronic (actual episode ≥2 years) or recurrent (history of at least 4 lifetime MDEs) disorder (N = 20), having a medical illness that contraindicated surgery (N = 4), or having a current Substance Use Disorder (N = 2). One additional patient, fulfilling eligibility criteria, first accepted to undergo surgical procedure, and then refused after the screening visit.
A total of five patients met the inclusion criteria and had the VNS generator implanted. The mean ± SD age of the patients was 56.6 ± 7.3 years (range, 48–66 years). Three patients had a Major Depressive Disorder (60.0%) and the remaining two patients had a Bipolar Disorder (one BD type I and one BD type II). Socio-demographic and clinical data are summarized in Table 1. Concerning the duration of the current MDE, three patients fulfilled DSM-IV criteria for chronic (>2 years) major depression (all three had a diagnosis of unipolar major depression). Pre-implant history of the two BD patients was carefully recorded by means of direct interview, family members' interview (when available) and medical records review. The first patient (Figure 1) had a history of BD type I with onset at age 26; he had more than 10 lifetime MDEs, with 8 admissions to psychiatric wards and 2 suicide attempts during previous episodes. Despite being on mood stabilizer (valproic acid), during the last two years preceding VNS implant he showed 3 MDEs (not considering the current one) without (hypo) manic episodes, but with intervals between depressive episodes lasting less than 3 months. Treatments with adjunctive lamotrigine or quetiapine did not result in stable remission; adjunctive antidepressants in the current episode did not resolve depressive symptomatology. The second patient (Figure 2) had BD type II, with onset at age 36. He also had more than 10 lifetime MDEs, a history of 1 prior suicide attempt, and had, during the last two years prior to VNS implant, 2 long-lasting MDEs (not considering the current one). He spent, during the last two years prior to surgery, a total of 5 months only without a MDE (although without complete remission), despite being treated with valproic acid, quetiapine, lamotrigine, and four different antidepressants (two of them during the current MDE). No hypomanic episodes were recorded in the last two years.
(Enlarge Image)
Figure 1.
HDRS, MADRS and CGI-S scores across time for Patient 4 (male, 57 years, Bipolar Disorder type I, comorbid Avoidant and Obsessive-Compulsive Personality Disorders).
(Enlarge Image)
Figure 2.
HDRS, MADRS and CGI-S scores across time for Patient 5 (male, 61 years, Bipolar Disorder type II, no comorbid diagnoses).
All patients had the VNS generator implanted but for the long-term follow-up, four patients (80.0%) were evaluable at 24 months and three (60.0%) were evaluable at 60 months. Two patients withdrew from the study: one subject (Figure 3), whose depression slightly improved (HDRS-17: 14), withdrew after 18 months because of side effects judged by the patient as intolerable (hoarseness, sore throat and neck pain), and had the VNS generator switched off. The other (Figure 2) withdrew after 12 months because symptoms remained unchanged (HDRS-17: 21); although the clinician in charge of that patient clearly advised him that VNS efficacy sometimes is evident after 12 months of treatment, he was unwilling to attend follow-up assessments and dropped out from the study.
(Enlarge Image)
Figure 3.
HDRS, MADRS and CGI-S scores across time for Patient 3 (female, 48 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
Table 2 shows results of the repeated measures ANOVA on the total scores of the HDRS, MADRS, CGI-S and SF-36 scales (all not statistically significant). Figures 1, 2, 3, 4 and 5 show individual scores for each patient and stimulation parameters, as patients had different outcomes over the 5-year follow-up. According to the HDRS-17, 2 patients were responders (40%) and remitters (40%) after 1 year of VNS treatment (patients 2 and 4). At 2 years, the three patients still on treatment were all responders and remitters. Two of the three patients who were followed-up for 5 years had one depressive recurrence during the 4th year and the third subject showed no recurrences for the whole period.
(Enlarge Image)
Figure 4.
HDRS, MADRS and CGI-S scores across time for Patient 1 (female, 66 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
(Enlarge Image)
Figure 5.
HDRS, MADRS and CGI-S scores across time for Patient 2 (female, 51 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
Table 3 summarizes the rates of adverse events (AEs) after VNS implant and during the follow-up period. With regard to tolerability, patients reported common side effects traditionally observed in previous clinical studies. The only side effect related to the surgical procedure was neck pain located at the level of the surgical incision, which generally disappeared within 2 weeks from implant. Only in one case the pain persisted up to month 18. Stimulation-related adverse effects experienced by patients were hoarseness, discomfort, sore throat, headache, alteration of voice, and described as mild to moderate. In one patient, hoarseness, sore throat and neck pain were described as severe and intolerable, and the patient asked to have the VNS generator switched off at 1 year; after 5 months we tried again to switch on the generator, but she reported again intolerable side effects and 18 months after the implant she asked to have the generator switched off definitely. Pulse-width was not reduced, although this strategy is commonly used to improve tolerability. No (hypo) manic episodes, a rare but yet documented adverse event potentially occurring with VNS, were observed during the 60 months of stimulation.
Results
One hundred-fifty-nine subjects were interviewed through telephone in order to assess eligibility criteria for inclusion into the study; of them, 39 were asked to present for a face-to-face clinical interview. Thirty-three patients were excluded because of not having a current Major Depressive Episode (N = 7), not having a chronic (actual episode ≥2 years) or recurrent (history of at least 4 lifetime MDEs) disorder (N = 20), having a medical illness that contraindicated surgery (N = 4), or having a current Substance Use Disorder (N = 2). One additional patient, fulfilling eligibility criteria, first accepted to undergo surgical procedure, and then refused after the screening visit.
A total of five patients met the inclusion criteria and had the VNS generator implanted. The mean ± SD age of the patients was 56.6 ± 7.3 years (range, 48–66 years). Three patients had a Major Depressive Disorder (60.0%) and the remaining two patients had a Bipolar Disorder (one BD type I and one BD type II). Socio-demographic and clinical data are summarized in Table 1. Concerning the duration of the current MDE, three patients fulfilled DSM-IV criteria for chronic (>2 years) major depression (all three had a diagnosis of unipolar major depression). Pre-implant history of the two BD patients was carefully recorded by means of direct interview, family members' interview (when available) and medical records review. The first patient (Figure 1) had a history of BD type I with onset at age 26; he had more than 10 lifetime MDEs, with 8 admissions to psychiatric wards and 2 suicide attempts during previous episodes. Despite being on mood stabilizer (valproic acid), during the last two years preceding VNS implant he showed 3 MDEs (not considering the current one) without (hypo) manic episodes, but with intervals between depressive episodes lasting less than 3 months. Treatments with adjunctive lamotrigine or quetiapine did not result in stable remission; adjunctive antidepressants in the current episode did not resolve depressive symptomatology. The second patient (Figure 2) had BD type II, with onset at age 36. He also had more than 10 lifetime MDEs, a history of 1 prior suicide attempt, and had, during the last two years prior to VNS implant, 2 long-lasting MDEs (not considering the current one). He spent, during the last two years prior to surgery, a total of 5 months only without a MDE (although without complete remission), despite being treated with valproic acid, quetiapine, lamotrigine, and four different antidepressants (two of them during the current MDE). No hypomanic episodes were recorded in the last two years.
(Enlarge Image)
Figure 1.
HDRS, MADRS and CGI-S scores across time for Patient 4 (male, 57 years, Bipolar Disorder type I, comorbid Avoidant and Obsessive-Compulsive Personality Disorders).
(Enlarge Image)
Figure 2.
HDRS, MADRS and CGI-S scores across time for Patient 5 (male, 61 years, Bipolar Disorder type II, no comorbid diagnoses).
All patients had the VNS generator implanted but for the long-term follow-up, four patients (80.0%) were evaluable at 24 months and three (60.0%) were evaluable at 60 months. Two patients withdrew from the study: one subject (Figure 3), whose depression slightly improved (HDRS-17: 14), withdrew after 18 months because of side effects judged by the patient as intolerable (hoarseness, sore throat and neck pain), and had the VNS generator switched off. The other (Figure 2) withdrew after 12 months because symptoms remained unchanged (HDRS-17: 21); although the clinician in charge of that patient clearly advised him that VNS efficacy sometimes is evident after 12 months of treatment, he was unwilling to attend follow-up assessments and dropped out from the study.
(Enlarge Image)
Figure 3.
HDRS, MADRS and CGI-S scores across time for Patient 3 (female, 48 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
Table 2 shows results of the repeated measures ANOVA on the total scores of the HDRS, MADRS, CGI-S and SF-36 scales (all not statistically significant). Figures 1, 2, 3, 4 and 5 show individual scores for each patient and stimulation parameters, as patients had different outcomes over the 5-year follow-up. According to the HDRS-17, 2 patients were responders (40%) and remitters (40%) after 1 year of VNS treatment (patients 2 and 4). At 2 years, the three patients still on treatment were all responders and remitters. Two of the three patients who were followed-up for 5 years had one depressive recurrence during the 4th year and the third subject showed no recurrences for the whole period.
(Enlarge Image)
Figure 4.
HDRS, MADRS and CGI-S scores across time for Patient 1 (female, 66 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
(Enlarge Image)
Figure 5.
HDRS, MADRS and CGI-S scores across time for Patient 2 (female, 51 years, Major Depressive Disorder, chronic MDE, no comorbid diagnoses).
Table 3 summarizes the rates of adverse events (AEs) after VNS implant and during the follow-up period. With regard to tolerability, patients reported common side effects traditionally observed in previous clinical studies. The only side effect related to the surgical procedure was neck pain located at the level of the surgical incision, which generally disappeared within 2 weeks from implant. Only in one case the pain persisted up to month 18. Stimulation-related adverse effects experienced by patients were hoarseness, discomfort, sore throat, headache, alteration of voice, and described as mild to moderate. In one patient, hoarseness, sore throat and neck pain were described as severe and intolerable, and the patient asked to have the VNS generator switched off at 1 year; after 5 months we tried again to switch on the generator, but she reported again intolerable side effects and 18 months after the implant she asked to have the generator switched off definitely. Pulse-width was not reduced, although this strategy is commonly used to improve tolerability. No (hypo) manic episodes, a rare but yet documented adverse event potentially occurring with VNS, were observed during the 60 months of stimulation.
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