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A randomized, crossover trial of deep brain stimulation of the ventral anterior limb of the internal capsule in depression
P.2.b. Mood disorders and treatment − Affective disorders (clinical) P.2.b.030 Peripapillary retinal nerve fiber layer thickness in major depressive patients treated with repetitive TMS M. Dalkiran Varkal1 ° , A. Genc1 , E. Pirdogan1 , E. Turkyılmaz Uyar1 , A. Alkan2 , D. Guven2 , O.A. Ozer1 1 Training and ˙ Research Hospital of S¸ i¸sli Hamidiye Etfal, Psychiatry, Istanbul, Turkey; 2 Training and Research Hospital of S¸ i¸sli Hamidiye Etfal, ˙ Ophthalmology, Istanbul, Turkey Background: Neuroimaging studies have found evidence of reduced volume of structures such as the amygdala, hippocampus and basal ganglia in the brain of patients with major depression [1]. The nerves and axons of the retinal nerve fiber layer (RNFL) are similar to those in the brain. RNFL thickness loss have been shown in neurodegenerative diseases, such as Parkinson’s, Alzheimer’s diseases, schizophrenia and bipolar disorder [2−5]. The aim of our study was to evaluate the RNFL thickness in the treatment resistant major depressive patients before and after repetitive transcranial magnetic stimulation treatment using spectral domain optical coherence tomography (SD-OCT), and to compare the peripapillary RNFL thickness between these patients and the normal control population. Method: Study groups were chosen in outpatients admitted to Sisli Etfal Education and Research State Hospital with treatment resistant major depressive disorder according to DSM IVTR criteria. Twenty-four patients with treatment resistant major depression and 24 age matched healthy controls were included in the study. Participants with conditions that might affect the retinal nerve fiber structures were excluded from the study. Patients were treated with antidepressants plus rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2−4 consecutive weeks and assessed with Hamilton Depression scale (HAM-D) and Hamilton Anxiety (HAM-A) scale before and after treatment. Peripapillary RNFL thickness of patients were measured with SD-OCT before and after treatment and compared with healthy controls. Results: Comparison of the peripapillery RNFL thickness using the independent t-test showed that the significantly increased RNFL thickness in the superior (patients, 140±20.7 mm; controls, 124±26.3 mm; P = 0.027), inferior (patients, 141±15.8 mm; controls, 130±15.5 mm; P = 0.017) and temporal (patients, 80.1±10 mm; controls, 70.4±11.1 mm; P = 0.003) quadrants in depressive patients than that in the control group. Comparison of RNFL thickness in the patients before and after repetitive transcranial magnetic stimulation showed statistically significant increase only in the inferior quadrant (pre-treatment, 141±15.8 mm; post-treatment, 146±18.8 mm; P = 0.036). No correlation was found between the RNFL thickness and the age, HAM-D, HAM-A scores, duration of the disease. Conclusion: Results of our study showed increased RNFL thickness in the superior, inferior and temporal quadrants of depressive patients compared with healthy controls and increased RNFL thickness in the inferior quadrant after antidepressants plus rTMS treatment. Recently published two studies showed a statistically significant reduction in peripapillary RNFL thickness and correlation with the disease duration in patients with schizophrenia and bipolar disorder which were inconsistent with our study [3,5]. Our results did not support the findings stated in the study of Fakhoury et al. [1], which were reduced volume of brain structures such as grey matter, amygdala, hippocampus, basal ganglia, thalamus and frontal cortex in the brain of patients with major depression.
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References [1] Fakhoury, M., 2015. New insights into the neurobiological mechanisms of major depressive disorders. Gen Hosp Psychiatry 37(2), 172–177. [2] Inzelberg, R., Ramirez, J.A., Nisipeanu, P., Ophir, A., 2004. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res. 44(24), 2793–2797. [3] Lee, W.W., Tajunisah, I., Sharmilla, K., Peyman, M., Subrayan, V., 2013. Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography Invest Ophthalmol Vis Sci. 54, 7785–7792. [4] Kromer, R., Serbecic, N., Hausner, L., Froelich, L., Aboul-Enein, F., Beutelspacher, S.C., 2014. Detection of Retinal Nerve Fiber Layer Defects in Alzheimer’s Disease Using SD-OCT Front Psychiatry. Feb 25, 5, 22. [5] Mehraban, A., Samimi, S.M., Entezari, M., Seifi, M.H., Nazari, M., Yaseri, M., 2016. Peripapillary retinal nerve fiber layer thickness in bipolar disorder Graefes Arch Clin Exp Ophthalmol. 254(2):365–371.
P.2.b.032 A randomized, crossover trial of deep brain stimulation of the ventral anterior limb of the internal capsule in depression I.O. Bergfeld1 ° , M. Mantione1 , D. Denys1,2 1 Academic Medical Center, Psychiatry, Amsterdam, The Netherlands; 2 Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands Background: Patients with Treatment Resistant Depression (TRD) do not respond sufficiently to several consecutive antidepressant treatments. In the past decade several open label trials have shown the promise of Deep Brain Stimulation (DBS) targeted to striatal, capsular and cingulate areas as a treatment for TRD [1]. However, placebo effects currently cannot be ruled out. Aim: Assessing the efficacy and tolerability of DBS of the ventral Anterior Limb of the Internal Capsule (vALIC). Methods: Twenty-five TRD patients were followed between March 2010 and May 2014. Patients underwent DBS targeted to the ventral Anterior Limb of the Internal Capsule (vALIC) with subsequent 52-week open-label DBS parameter optimization. Subsequently, patients entered a crossover phase, in which they were randomized to active and then sham stimulation or vice versa. Patients, raters and health care professionals were kept blind for the stimulation setting. Analysis: In the open phase, we analyzed change of Hamilton Depression Rating Scale (HAM-D) score (range 0−52, higher scores indicating more symptoms) over the course of the optimization phase. In addition, we classified patients as responders (50% decrease of HAM-D compared to baseline) and partial responders (25, but <50% decrease) following the optimization phase in an intention-to-treat analysis. In the crossover phase, we analyzed the difference of HAM-D scores between active and sham stimulation, correcting for order, carry-over effects and scores at the start of the crossover phase. Results: Average HAM-D scores decreased from 22.2 (SD: 4.9) to 15.9 (SD: 9.2) over the course of the optimization phase (P < 0.001). Ten patients (40%) were classified as responders and 6 as partial responders (24%) after optimizing DBS parameters. Serious adverse events during the optimization phase were suicide attempts (4 patients), and increased suicidality requiring hospitalization (2 patients). Sixteen of the 25 patients entered the randomized cross-over phase (nine responders, seven nonresponders). During sham stimulation patients scored significantly higher on the HAM-D (M: 23.1, SD: 5.1) than during active stimulation (M: 13.6, SD: 7.8, P < 0.001). No serious adverse events were recorded during the crossover phase. Adverse events
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P.2.b. Mood disorders and treatment − Affective disorders (clinical)
that occurred in the active phase only were sleep disturbances (3 patients), blurred vision (2 patients), and disinhibition (e.g. extremely talkative, 2 patients). Discussion: vALIC DBS resulted in significant decrease of depressive symptoms in ten of 25 patients and was tolerated well. The randomized cross-over phase corroborates that vALIC DBS causes the symptom reduction rather than placebo. These results are at odds with a recently published randomized controlled trial of ventral capsule/ventral striatum DBS [2], who found no differences between active and sham stimulation. Possible reasons could be the somewhat more anterior placement of the electrodes in our study or differences between studies in strategies to optimize DBS parameters. This study confirms the promise of DBS and in light of previous research calls for further specification of targets and optimization strategies. Trial registration: Dutch Trial Register, Nr. 2118, http:// www.trialregister.nl/trialreg/admin/rctview.asp?TC=2118 References [1] Schlaepfer, T.E., Bewernick, B.H., Kayser, S., Hurlemann, R., Coenen, V.A., 2014. Deep brain stimulation of the human reward system for major depression − rationale, outcomes and outlook. Neuropsychopharmacology 39, 1303−14. [2] Dougherty, D.D., Rezai, A.R., Carpenter, L.L., Howland, R.H., Bhati, M.T., O’Reardon, J.P., Eskandar, E.N., Baltuch, G.H., Machado, A.D., Kondziolka, D., Cusin, C., Evans, K.C., Price, L.H., Jacobs, K., Pandya, M., Denko, T., Tyrka, A.R., Brelje, T., Deckersbach, T., Kubu, C., Malone, D. a., 2015. A Randomized ShamControlled Trial of Deep Brain Stimulation of the Ventral Capsule/ Ventral Striatum for Chronic Treatment-Resistant Depression. Biol. Psychiatry 78, 240−8.
P.2.b.033 Assessing affective disorders through speech analysis: a self-assessment “voice app” for laptops, tablets, and smartphones S. Braun1 , C. Mohr2 , I. Moragrega3 , C. Papagno4 , H.H. Stassen1 ° University Hospital KPPP, Institute for ResponseGenetics, Kilchberg, Switzerland; 2 University of Lausanne, Psychology, Lausanne, Switzerland; 3 University of Valencia, Pharmacology, Valencia, Spain; 4 University of Milano-Bicocca, Psychology, Milano, Italy 1 Psychiatric
Background: Human speech is greatly influenced by the speakers’ affective state which reflects feelings like chronic stress, sadness, happiness, grief, guilt, fear, anger, aggression, faintheartedness, shame, love, or doziness — and, occasionally, by depressive or psychotic symptoms. Computerized speech analysis (CSA) is a clinically proven method that allows one to assess stressinduced mood disturbances and affective disorders in an “objective” way [1−4]. This project aimed to extend the CSA method in such a way that the transition from “normal” to “affected” can be detected among subjects of the general population through selfassessments. Methods: Central to the project was a normative speech study of 697 subjects of 5 major languages (English, French, German, Italian, Spanish) and stratified according to gender, age, and education. Each test person presented 3 different types of text twice at an interval of 14 days: counting out loud from 1 to 40, reading out loud an emotionally neutral passage of a children’s book, and reading out loud an emotionally stimulating passage from a famous novel. Additionally, test persons were asked to fill out the 63-item Zurich Health Questionnaire (ZHQ) so that subjects with mental health problems could be excluded. Based on these data, we developed a multivariate model assessing affective states
and stress-induced behavior through speaking behavior and voice sound characteristics. We determined language-, gender-, and agespecific thresholds that allowed us to draw a line between “natural fluctuations” and “significant changes”. We then implemented the model and normative data in a self-assessment “voice app” for laptops, tablets, and smartphones. Finally, we carried out a longitudinal self-assessment study of 36 subjects over 14 days with daily assessments to test the performance of the newly developed method in home environments. Results: The data showed that speaking behavior and voice sound characteristics can be quantified in a highly reliable and language-independent way. Gender and age explained as much as 15−35% of the observed variance, whereas educational level had a relatively small effect in the range of 1−3%. The selfassessment “voice app” was realized in modular form so that additional languages can simply be “plugged-in”, once the respective normative data are available. Results of the longitudinal self-assessment study in home environments demonstrated that the method worked well under most circumstances. Conclusions: We have successfully developed and tested a CSA method that can detect the transition from “normal” to “affected” in subjects of the general population who are at risk of affective disorders. The easy-to-use self-assessment “voice app” allows users to detect affect- and stress-induced deviations from baseline that exceed the language-, gender-, and age-specific thresholds defined by our normative data. We expect that this “voice app” can help to identify that 10−15% subgroup of the general population that exhibits insufficient coping skills under chronic stress and an elevated risk of developing affective disorders. These subjects will clearly benefit from early detection and intervention prior to developing clinically relevant symptoms. References [1] Braun, S., Botella, C., Bridler, R., Chmetz, F., Delfino, J.P., Herzig, D., Kluckner, V.J., Mohr, C., Moragrega, I., Schrag, Y., Seifritz, E., Soler, C., Stassen, H.H., 2014. Affective State and Voice: CrossCultural Assessment of Speaking Behavior and Voice Sound Characteristics. A Normative Multi-Center Study of 577+36 Healthy Subjects. Psychopathology 47(5): 327–340. [2] Stassen, H.H., Angst, J., Hell, D., Scharfetter, C., Szegedi, A. 2007. Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry, 68(8): 1195– 1205. [3] Stassen, H.H., Kuny, S., Hell, D., 1998. The speech analysis approach to determining onset of improvement under antidepressants. Eur Neuropsychopharmacology, 8, 4: 303–310. [4] Mundt, J.C., Vogel, A.P., Feltner, D.E., Lenderking, W.R., 2012. Vocal acoustic biomarkers of depression severity and treatment response. Biol Psychiatry, 72(7): 580–587. Disclosure statement: This project was funded in part through the 7th EU Framework Programme for Research and Technological Development (grant 248544 OPTIMI: “http://www.ifrg.uzh.ch/optimi.php”).
P.2.b.034 Cognitive and emotional deficits: a comparison between bipolar and schizoaffective patients R. Romosan1 ° , A. Draghici2,3 , F. Romosan1 , V. Enatescu1 , L. Dehelean1 , A. Bredicean1 , I. Papava1 , M. Manea3 1 Victor Babes University of Medicine and Pharmacy of Timi¸soara, Neuroscience, Timisoara, Romania; 2 PhD Candidate- “Vasile Goldis” University of Medicine and Pharmacy, Neuroscience, Arad, Romania; 3 Timisoara Psychiatric Clinic, Neuroscience, Timisoara, Romania Background: Both bipolar and schizoaffective patients suffer cognitive impairment during the acute episode, but also in euthymic
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References [1] Fakhoury, M., 2015. New insights into the neurobiological mechanisms of major depressive disorders. Gen Hosp Psychiatry 37(2), 172–177. [2] Inzelberg, R., Ramirez, J.A., Nisipeanu, P., Ophir, A., 2004. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res. 44(24), 2793–2797. [3] Lee, W.W., Tajunisah, I., Sharmilla, K., Peyman, M., Subrayan, V., 2013. Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography Invest Ophthalmol Vis Sci. 54, 7785–7792. [4] Kromer, R., Serbecic, N., Hausner, L., Froelich, L., Aboul-Enein, F., Beutelspacher, S.C., 2014. Detection of Retinal Nerve Fiber Layer Defects in Alzheimer’s Disease Using SD-OCT Front Psychiatry. Feb 25, 5, 22. [5] Mehraban, A., Samimi, S.M., Entezari, M., Seifi, M.H., Nazari, M., Yaseri, M., 2016. Peripapillary retinal nerve fiber layer thickness in bipolar disorder Graefes Arch Clin Exp Ophthalmol. 254(2):365–371.
P.2.b.032 A randomized, crossover trial of deep brain stimulation of the ventral anterior limb of the internal capsule in depression I.O. Bergfeld1 ° , M. Mantione1 , D. Denys1,2 1 Academic Medical Center, Psychiatry, Amsterdam, The Netherlands; 2 Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands Background: Patients with Treatment Resistant Depression (TRD) do not respond sufficiently to several consecutive antidepressant treatments. In the past decade several open label trials have shown the promise of Deep Brain Stimulation (DBS) targeted to striatal, capsular and cingulate areas as a treatment for TRD [1]. However, placebo effects currently cannot be ruled out. Aim: Assessing the efficacy and tolerability of DBS of the ventral Anterior Limb of the Internal Capsule (vALIC). Methods: Twenty-five TRD patients were followed between March 2010 and May 2014. Patients underwent DBS targeted to the ventral Anterior Limb of the Internal Capsule (vALIC) with subsequent 52-week open-label DBS parameter optimization. Subsequently, patients entered a crossover phase, in which they were randomized to active and then sham stimulation or vice versa. Patients, raters and health care professionals were kept blind for the stimulation setting. Analysis: In the open phase, we analyzed change of Hamilton Depression Rating Scale (HAM-D) score (range 0−52, higher scores indicating more symptoms) over the course of the optimization phase. In addition, we classified patients as responders (50% decrease of HAM-D compared to baseline) and partial responders (25, but <50% decrease) following the optimization phase in an intention-to-treat analysis. In the crossover phase, we analyzed the difference of HAM-D scores between active and sham stimulation, correcting for order, carry-over effects and scores at the start of the crossover phase. Results: Average HAM-D scores decreased from 22.2 (SD: 4.9) to 15.9 (SD: 9.2) over the course of the optimization phase (P < 0.001). Ten patients (40%) were classified as responders and 6 as partial responders (24%) after optimizing DBS parameters. Serious adverse events during the optimization phase were suicide attempts (4 patients), and increased suicidality requiring hospitalization (2 patients). Sixteen of the 25 patients entered the randomized cross-over phase (nine responders, seven nonresponders). During sham stimulation patients scored significantly higher on the HAM-D (M: 23.1, SD: 5.1) than during active stimulation (M: 13.6, SD: 7.8, P < 0.001). No serious adverse events were recorded during the crossover phase. Adverse events
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P.2.b. Mood disorders and treatment − Affective disorders (clinical)
that occurred in the active phase only were sleep disturbances (3 patients), blurred vision (2 patients), and disinhibition (e.g. extremely talkative, 2 patients). Discussion: vALIC DBS resulted in significant decrease of depressive symptoms in ten of 25 patients and was tolerated well. The randomized cross-over phase corroborates that vALIC DBS causes the symptom reduction rather than placebo. These results are at odds with a recently published randomized controlled trial of ventral capsule/ventral striatum DBS [2], who found no differences between active and sham stimulation. Possible reasons could be the somewhat more anterior placement of the electrodes in our study or differences between studies in strategies to optimize DBS parameters. This study confirms the promise of DBS and in light of previous research calls for further specification of targets and optimization strategies. Trial registration: Dutch Trial Register, Nr. 2118, http:// www.trialregister.nl/trialreg/admin/rctview.asp?TC=2118 References [1] Schlaepfer, T.E., Bewernick, B.H., Kayser, S., Hurlemann, R., Coenen, V.A., 2014. Deep brain stimulation of the human reward system for major depression − rationale, outcomes and outlook. Neuropsychopharmacology 39, 1303−14. [2] Dougherty, D.D., Rezai, A.R., Carpenter, L.L., Howland, R.H., Bhati, M.T., O’Reardon, J.P., Eskandar, E.N., Baltuch, G.H., Machado, A.D., Kondziolka, D., Cusin, C., Evans, K.C., Price, L.H., Jacobs, K., Pandya, M., Denko, T., Tyrka, A.R., Brelje, T., Deckersbach, T., Kubu, C., Malone, D. a., 2015. A Randomized ShamControlled Trial of Deep Brain Stimulation of the Ventral Capsule/ Ventral Striatum for Chronic Treatment-Resistant Depression. Biol. Psychiatry 78, 240−8.
P.2.b.033 Assessing affective disorders through speech analysis: a self-assessment “voice app” for laptops, tablets, and smartphones S. Braun1 , C. Mohr2 , I. Moragrega3 , C. Papagno4 , H.H. Stassen1 ° University Hospital KPPP, Institute for ResponseGenetics, Kilchberg, Switzerland; 2 University of Lausanne, Psychology, Lausanne, Switzerland; 3 University of Valencia, Pharmacology, Valencia, Spain; 4 University of Milano-Bicocca, Psychology, Milano, Italy 1 Psychiatric
Background: Human speech is greatly influenced by the speakers’ affective state which reflects feelings like chronic stress, sadness, happiness, grief, guilt, fear, anger, aggression, faintheartedness, shame, love, or doziness — and, occasionally, by depressive or psychotic symptoms. Computerized speech analysis (CSA) is a clinically proven method that allows one to assess stressinduced mood disturbances and affective disorders in an “objective” way [1−4]. This project aimed to extend the CSA method in such a way that the transition from “normal” to “affected” can be detected among subjects of the general population through selfassessments. Methods: Central to the project was a normative speech study of 697 subjects of 5 major languages (English, French, German, Italian, Spanish) and stratified according to gender, age, and education. Each test person presented 3 different types of text twice at an interval of 14 days: counting out loud from 1 to 40, reading out loud an emotionally neutral passage of a children’s book, and reading out loud an emotionally stimulating passage from a famous novel. Additionally, test persons were asked to fill out the 63-item Zurich Health Questionnaire (ZHQ) so that subjects with mental health problems could be excluded. Based on these data, we developed a multivariate model assessing affective states
and stress-induced behavior through speaking behavior and voice sound characteristics. We determined language-, gender-, and agespecific thresholds that allowed us to draw a line between “natural fluctuations” and “significant changes”. We then implemented the model and normative data in a self-assessment “voice app” for laptops, tablets, and smartphones. Finally, we carried out a longitudinal self-assessment study of 36 subjects over 14 days with daily assessments to test the performance of the newly developed method in home environments. Results: The data showed that speaking behavior and voice sound characteristics can be quantified in a highly reliable and language-independent way. Gender and age explained as much as 15−35% of the observed variance, whereas educational level had a relatively small effect in the range of 1−3%. The selfassessment “voice app” was realized in modular form so that additional languages can simply be “plugged-in”, once the respective normative data are available. Results of the longitudinal self-assessment study in home environments demonstrated that the method worked well under most circumstances. Conclusions: We have successfully developed and tested a CSA method that can detect the transition from “normal” to “affected” in subjects of the general population who are at risk of affective disorders. The easy-to-use self-assessment “voice app” allows users to detect affect- and stress-induced deviations from baseline that exceed the language-, gender-, and age-specific thresholds defined by our normative data. We expect that this “voice app” can help to identify that 10−15% subgroup of the general population that exhibits insufficient coping skills under chronic stress and an elevated risk of developing affective disorders. These subjects will clearly benefit from early detection and intervention prior to developing clinically relevant symptoms. References [1] Braun, S., Botella, C., Bridler, R., Chmetz, F., Delfino, J.P., Herzig, D., Kluckner, V.J., Mohr, C., Moragrega, I., Schrag, Y., Seifritz, E., Soler, C., Stassen, H.H., 2014. Affective State and Voice: CrossCultural Assessment of Speaking Behavior and Voice Sound Characteristics. A Normative Multi-Center Study of 577+36 Healthy Subjects. Psychopathology 47(5): 327–340. [2] Stassen, H.H., Angst, J., Hell, D., Scharfetter, C., Szegedi, A. 2007. Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry, 68(8): 1195– 1205. [3] Stassen, H.H., Kuny, S., Hell, D., 1998. The speech analysis approach to determining onset of improvement under antidepressants. Eur Neuropsychopharmacology, 8, 4: 303–310. [4] Mundt, J.C., Vogel, A.P., Feltner, D.E., Lenderking, W.R., 2012. Vocal acoustic biomarkers of depression severity and treatment response. Biol Psychiatry, 72(7): 580–587. Disclosure statement: This project was funded in part through the 7th EU Framework Programme for Research and Technological Development (grant 248544 OPTIMI: “http://www.ifrg.uzh.ch/optimi.php”).
P.2.b.034 Cognitive and emotional deficits: a comparison between bipolar and schizoaffective patients R. Romosan1 ° , A. Draghici2,3 , F. Romosan1 , V. Enatescu1 , L. Dehelean1 , A. Bredicean1 , I. Papava1 , M. Manea3 1 Victor Babes University of Medicine and Pharmacy of Timi¸soara, Neuroscience, Timisoara, Romania; 2 PhD Candidate- “Vasile Goldis” University of Medicine and Pharmacy, Neuroscience, Arad, Romania; 3 Timisoara Psychiatric Clinic, Neuroscience, Timisoara, Romania Background: Both bipolar and schizoaffective patients suffer cognitive impairment during the acute episode, but also in euthymic