Vagus Nerve Stimulation for Resistant Mood Disorders
Vagus Nerve Stimulation for Resistant Mood Disorders
Participants were recruited consecutively from January 2007 to May 2008 among subjects referred to the Mood and Anxiety Disorders Unit of the Department of Neuroscience, University of Turin (Italy); this is a tertiary referral centre located within the University Hospital and specialized in the treatment of patients with Mood Disorders.
The aims of the study as well as study procedures were thoroughly explained to potential participants who gave written consent before participation. The study design was reviewed and approved by the local ethics committee (Comitato Etico Interaziendale A.O.U. Città della Salute e della Scienza di Torino - A.O. Ordine Mauriziano - A.S.L. TO1).
To be enrolled in the study, patients fulfilled the following inclusion criteria: a) a current Major Depressive Episode, chronic (actual episode ≥2 years) or recurrent (history of at least 4 lifetime MDEs), according to the Structured Clinical Interview for Axis I Disorders (SCID-I/P – DSM IV TR); b) 18 years of age or older; c) during the current MDE, failure to respond to at least two adequate trials of antidepressant treatments; d) a minimum total score of 20 on the HDRS; and e) stable psychopharmacological medication for at least 4 weeks before baseline. We defined non-responder a patient who failed to show a reduction of the 17-item HDRS total score ≥50% with respect to the beginning of the pharmacological trial. We considered an adequate antidepressant trial, according to Sackeim, a full-dosage antidepressant given for at least 4 weeks. We also required that patients took two antidepressants of different pharmacological classes.
Exclusion criteria were: 1) past or current presence of psychotic features; 2) suicide attempt requiring medical treatment within the previous twelve months; 3) history of schizophrenia, schizoaffective disorder or rapid cycling bipolar disorder; 4) severe Axis II disorders (such as borderline or antisocial); 5) alcohol or substance dependence within the previous twelve months or abuse of a substance other than nicotine during the previous six months; 6) diagnosis or signs of delirium, dementia, or amnestic and other cognitive disorders; 7) previous head injuries, cardiac or neurological diseases, and surgical implantation-related risks.
All patients were on antidepressants (with or without mood-stabilizers depending on the diagnosis of MDD or BD), which were not withdrawn after surgery. Throughout the follow-up period, the dosage of antidepressant medications was adjusted according to clinical condition, while no change of type of antidepressant treatment or mood-stabilizer was performed during the first year after surgery.
Unmasked clinical outcome measures included the 17-item Hamilton Rating Scale for Depression (HDRS-17), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) scale. These measurements were obtained at pre-treatment (baseline), at post-surgery (2 weeks after implantation), every three months for the first two years and then annually. During the first 12 months, a self-report measure of quality of life was also administered: the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). The SF-36 contains 8 scales for assessing physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Summary scales include a physical composite and a mental composite that are expressed as t scores (mean = 50, SD = 10).
Response was defined as a reduction of the 17-item HDRS total score ≥50% with respect to baseline, remission as a score ≤7.
In addition, tolerability and side effects were recorded. Adverse events were defined as events occurring on or after the date of implantation, events not reported as signs or symptoms at baseline and/or worsening in severity or frequency. Presence of mania was monitored using the Young Mania Rating Scale (YMRS): a score of 12 was used as the threshold for the diagnosis of mania.
The device component consists of a pulse generator with a lithium battery and a lead wire with two helical electrodes and a tethering anchor. Under operating microscope the helical electrodes and the anchor tether coil were wrapped around the left cervical vagus nerve and a strain relief bend of lead to provide slack during movement of the neck was created. The lead connector pin was attached to a generator situated subcutaneously in the left thoracic region. The electrical connections of the whole device were then checked with a system diagnostic performed with the wand and programming computer. During the electro-diagnostic test the pulse generator delivered 1 mA output current at 20 Hz with a pulse width of 500 μsec and measured the impedance. At this moment the heart rate was monitored to highlight a possible bradycardia. The pulse generator was then inserted into the subcutaneous pocket and the two wounds closed in anatomical layers using absorbable suture and paying attention to a good cosmetic result. The generator was switched off for two weeks postoperatively to allow postsurgical edema to resolve.
Subjects' characteristics were summarized as mean and SD for continuous variables and frequency and percentage for categorical variables. A repeated measures ANOVA was performed on total scores of the HDRS, MADRS and CGI-S scales before (baseline, surgery) and after 3, 6, 9 and 12 months from VNS implant.
Methods
Participants
Participants were recruited consecutively from January 2007 to May 2008 among subjects referred to the Mood and Anxiety Disorders Unit of the Department of Neuroscience, University of Turin (Italy); this is a tertiary referral centre located within the University Hospital and specialized in the treatment of patients with Mood Disorders.
The aims of the study as well as study procedures were thoroughly explained to potential participants who gave written consent before participation. The study design was reviewed and approved by the local ethics committee (Comitato Etico Interaziendale A.O.U. Città della Salute e della Scienza di Torino - A.O. Ordine Mauriziano - A.S.L. TO1).
To be enrolled in the study, patients fulfilled the following inclusion criteria: a) a current Major Depressive Episode, chronic (actual episode ≥2 years) or recurrent (history of at least 4 lifetime MDEs), according to the Structured Clinical Interview for Axis I Disorders (SCID-I/P – DSM IV TR); b) 18 years of age or older; c) during the current MDE, failure to respond to at least two adequate trials of antidepressant treatments; d) a minimum total score of 20 on the HDRS; and e) stable psychopharmacological medication for at least 4 weeks before baseline. We defined non-responder a patient who failed to show a reduction of the 17-item HDRS total score ≥50% with respect to the beginning of the pharmacological trial. We considered an adequate antidepressant trial, according to Sackeim, a full-dosage antidepressant given for at least 4 weeks. We also required that patients took two antidepressants of different pharmacological classes.
Exclusion criteria were: 1) past or current presence of psychotic features; 2) suicide attempt requiring medical treatment within the previous twelve months; 3) history of schizophrenia, schizoaffective disorder or rapid cycling bipolar disorder; 4) severe Axis II disorders (such as borderline or antisocial); 5) alcohol or substance dependence within the previous twelve months or abuse of a substance other than nicotine during the previous six months; 6) diagnosis or signs of delirium, dementia, or amnestic and other cognitive disorders; 7) previous head injuries, cardiac or neurological diseases, and surgical implantation-related risks.
All patients were on antidepressants (with or without mood-stabilizers depending on the diagnosis of MDD or BD), which were not withdrawn after surgery. Throughout the follow-up period, the dosage of antidepressant medications was adjusted according to clinical condition, while no change of type of antidepressant treatment or mood-stabilizer was performed during the first year after surgery.
Clinical Assessment
Unmasked clinical outcome measures included the 17-item Hamilton Rating Scale for Depression (HDRS-17), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) scale. These measurements were obtained at pre-treatment (baseline), at post-surgery (2 weeks after implantation), every three months for the first two years and then annually. During the first 12 months, a self-report measure of quality of life was also administered: the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). The SF-36 contains 8 scales for assessing physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Summary scales include a physical composite and a mental composite that are expressed as t scores (mean = 50, SD = 10).
Response was defined as a reduction of the 17-item HDRS total score ≥50% with respect to baseline, remission as a score ≤7.
In addition, tolerability and side effects were recorded. Adverse events were defined as events occurring on or after the date of implantation, events not reported as signs or symptoms at baseline and/or worsening in severity or frequency. Presence of mania was monitored using the Young Mania Rating Scale (YMRS): a score of 12 was used as the threshold for the diagnosis of mania.
Operative Procedure
The device component consists of a pulse generator with a lithium battery and a lead wire with two helical electrodes and a tethering anchor. Under operating microscope the helical electrodes and the anchor tether coil were wrapped around the left cervical vagus nerve and a strain relief bend of lead to provide slack during movement of the neck was created. The lead connector pin was attached to a generator situated subcutaneously in the left thoracic region. The electrical connections of the whole device were then checked with a system diagnostic performed with the wand and programming computer. During the electro-diagnostic test the pulse generator delivered 1 mA output current at 20 Hz with a pulse width of 500 μsec and measured the impedance. At this moment the heart rate was monitored to highlight a possible bradycardia. The pulse generator was then inserted into the subcutaneous pocket and the two wounds closed in anatomical layers using absorbable suture and paying attention to a good cosmetic result. The generator was switched off for two weeks postoperatively to allow postsurgical edema to resolve.
Statistical Analysis
Subjects' characteristics were summarized as mean and SD for continuous variables and frequency and percentage for categorical variables. A repeated measures ANOVA was performed on total scores of the HDRS, MADRS and CGI-S scales before (baseline, surgery) and after 3, 6, 9 and 12 months from VNS implant.
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