Effets neurophysiologiques de la stimulation du nerf vague : implication dans le traitement de la dépression résistante et optimisation des paramètres de stimulation

La dépression est une pathologie grave qui, malgré de multiples stratégies thérapeutiques, demeure résistante chez un tiers des patients. Les techniques de stimulation cérébrale sont devenues une alternative intéressante pour les patients résistants à diverses pharmacothérapies. La stimulation du nerf vague (SNV) a ainsi fait preuve de son efficacité en clinique et a récemment été approuvée comme traitement additif pour la dépression résistante. Cependant, les mécanismes d’action de la SNV en rapport avec la dépression n’ont été que peu étudiés. Cette thèse a donc eu comme premier objectif de caractériser l’impact de la SNV sur les différents systèmes monoaminergiques impliqués dans la pathophysiologie de la dépression, à savoir la sérotonine (5-HT), la noradrénaline (NA) et la dopamine (DA), grâce à l’utilisation de techniques électrophysiologiques et de la microdialyse in vivo chez le rat. Des études précliniques avaient déjà révélé qu’une heure de SNV augmente le taux de décharge des neurones NA du locus coeruleus, et que 14 jours de stimulation sont nécessaires pour observer un effet comparable sur les neurones 5-HT. Notre travail a démontré que la SNV modifie aussi le mode de décharge des neurones NA qui présente davantage de bouffées, influençant ainsi la libération terminale de NA, qui est significativement augmentée dans le cortex préfrontal et l’hippocampe après 14 jours. L’augmentation de la neurotransmission NA s’est également manifestée par une élévation de l’activation tonique des récepteurs postsynaptiques α2-adrénergiques de l’hippocampe. Après lésion des neurones NA, nous avons montré que l’effet de la SNV sur les neurones 5-HT était indirect, et médié par le système NA, via l’activation des récepteurs α1-adrénergiques présents sur les neurones du raphé. Aussi, tel que les antidépresseurs classiques, la SNV augmente l’activation tonique des hétérorécepteurs pyramidaux 5-HT1A, dont on connait le rôle clé dans la réponse thérapeutique aux antidépresseurs. Par ailleurs, nous avons constaté que malgré une diminution de l’activité électrique des neurones DA de l’aire tegmentale ventrale, la SNV induit une augmentation de la DA extracellulaire dans le cortex préfrontal et particulièrement dans le noyau accumbens, lequel joue un rôle important dans les comportements de récompense et l’hédonie. Un deuxième objectif a été de caractériser les paramètres optimaux de SNV agissant sur la dépression, en utilisant comme indicateur le taux de décharge des neurones 5-HT. Des modalités de stimulation moins intenses se sont avérées aussi efficaces que les stimulations standards pour augmenter l’activité électrique des neurones 5-HT. Ces nouveaux paramètres de stimulation pourraient s’avérer bénéfiques en clinique, chez des patients ayant déjà répondu à la SNV. Ils pourraient minimiser les effets secondaires reliés aux périodes de stimulation et améliorer ainsi la qualité de vie des patients. Ainsi, ces travaux de thèse ont caractérisé l’influence de la SNV sur les trois systèmes monoaminergiques, laquelle s’avère en partie distincte de celle des antidépresseurs classiques tout en contribuant à son efficacité en clinique. D’autre part, les modalités de stimulation que nous avons définies seraient intéressantes à tester chez des patients recevant la SNV, car elles devraient contribuer à l’amélioration des bénéfices cliniques de cette thérapie.

Brief behavioural activation for adolescent depression: working with complexity and risk

Given the long-term negative outcomes associated with depression in adolescence, there is a pressing need to develop brief, evidence based treatments that are accessible to more young people experiencing low mood. Behavioural Activation (BA) is an effective treatment for adult depression, however little research has focused on the use of BA with depressed adolescents, particularly with briefer forms of BA. In this article we outline an adaptation of brief Behavioral Activation Treatment of Depression (BATD) designed for adolescents and delivered in eight sessions (Brief BA). This case example illustrates how a structured, brief intervention was useful for a depressed young person with a number of complicating and risk factors.

Detection of depression in patients with low vision

Purpose. Depression is common in people with vision impairment and further reduces levels of functioning independent of vision loss. However, depression most often remains undetected and untreated this group. Eye health  professionals (EHPs) (ophthalmic nurses, ophthalmologists, optometrists, and orthoptists) and rehabilitation workers (RWs) may be able to play a role in detecting depression. This study aimed to identify current practice and investigate factors associated with depression management strategies.
Methods. A self-administered cross-sectional survey of EHPs and RWs assessed current practice including confidence in working with depressed people with vision impairment; barriers to recognition, assessment, and management of depression; beliefs about the consequences, duration, and efficacy of treatment for depression in individuals with vision impariment.
Results. Ninety-four participants aged 23 to 69 years took part. Thirty-seven participants (39.8%) stated that they attempted to identify depression as part of patient management, with RWs significantly more likely to do so (n = 17, 60.7%) than EHPs (n = 20, 30.8%; p = 0.007). Intention to identify depression was not associated with sociodemographic factors, professional experience in eye care services, or the length and number of patient consultations, but a significant relationship was found for confidence, barriers, and beliefs about depression (p < 0.05). No consistent depression management strategy emerged and a range of barriers were highlighted.
Conclusions. Training programs are needed to provide EHPs and RWs with the skills and resources to address depression in people with vision loss under their care and to support the development of procedures by which concerns about depression can be identified objectively, documented, and included as part of a referral to appropriate services.

Motivational interviewing and cognitive behaviour therapy in the treatment of adolescent overweight and obesity : study design and methodology

Background

Despite the high prevalence and negative physical and psychosocial consequences of overweight and obesity in adolescents, very little research has evaluated treatment in this population. Consequently, clinicians working with overweight and obese adolescents have little empirical research on which to base their practise. Cognitive behavioural therapy has demonstrated efficacy in promoting behaviour change in many treatment resistant disorders. Motivational interviewing has been used to increase motivation for change and improve treatment outcomes. In this paper we describe the rationale and design of a randomised controlled trial testing the efficacy of motivational interviewing and cognitive behaviour therapy in the treatment of overweight and obese adolescents.
Methods

Participants took part in a motivational interview or a standard semi-structured assessment interview and were then randomly allocated to a cognitive behavioural intervention or a wait-list control condition. The cognitive behavioural intervention, the CHOOSE HEALTH Program, consisted of 13 individual treatment sessions (12 face-to-face, 1 phone call) followed by 9 maintenance sessions (7 phone calls, 2 face-to-face). Assessments were conducted prior to participation, after the treatment phase and after the maintenance phase of intervention. Improvement in body composition was the primary outcome; secondary outcomes included improved cardiovascular fitness, eating and physical activity habits, family and psychosocial functioning.
Conclusion

Despite the demonstrated effectiveness of motivational interviewing and cognitive behavioural therapy in the long-term management of many treatment resistant disorders, these approaches have been under-utilised in adolescent overweight and obesity treatment. This study provides baseline data and a thorough review of the study design and treatment approach to allow for the assessment of the efficacy of motivational interviewing and cognitive behavioural therapy in the treatment of adolescent overweight and obesity. Data obtained in this study will also provide much needed information about the behavioural and psychosocial factors associated with adolescent overweight and obesity.

Detecting and treating depression in people with mild intellectual disability : the views of key stakeholders

There is a pressing need for the development of programs for the early identification and treatment of depression in individuals with mild intellectual disability. The aim of this study was to ascertain the perspective of 64 key stakeholders (people with intellectual disability, healthcare professionals, family/caregivers & support workers) regarding the risk factors and characteristics of depression, the support and service needs of individuals with intellectual disability/depression and those who care for them. Findings enhance our understanding of depression and its risk factors in people with mild intellectual disability and endorse the need for the development of screening and intervention programs suitable for delivery by staff in agencies providing services to people with mild intellectual disability.

Vitamin D deficiency may play a role in depression

Vitamin D is known to be widely deficient in Western populations. The implications of this in terms of bone health are increasingly understood, yet its impact on other health areas, particularly mental health, is unclear. Recent data suggests that hypovitaminosis D may be common, especially in the elderly. Other studies have suggested that low levels of vitamin D are associated with poor mood. There are a number of trials that have suggested a role for Vitamin D in the supplementary treatment of depression. Dose may be a critical issue, as sun exposure and dietary intake may be low and high doses may be required.

N-acetyl cysteine for depressive symptoms in bipolar disorder - a double blind, randomized, placebo-controlled trial

Background: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorderare complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Methods: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.

Results: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: 8.05 [13.16, 2.95], p .002) a n d most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p .968) and no significant between-group differences inadverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.

Conclusions: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar  disorder.

Managing depression in patients with vision impairment : a descriptive study of practitioners' beliefs and confidence

Aim: Depression is common in older adults with vision impairment yet it often remains unidentified and untreated.
Eye health professionals (EHPs) and rehabilitation workers (RWs) may be able to assist in detecting depression. This study identified EHPs’ and RWs’ beliefs about depression and confidence in working with patients with vision
impairment and depression.
Methods: A self-administered cross-sectional survey of 94 EHPs and RWs assessed beliefs about the symptoms and treatment for depression, and confidence in working with depressed people with vision impairment.
Results: Participants showed awareness of both the symptoms and treatment options for depression. However,
some important misconceptions were identified and many symptoms of depression were commonly attributed to
vision loss. Participants lacked confidence in communicating about depression with patients and their families.
Conclusions: Training programs are needed to enable EHPs and RWs to confidently identify depression and
discuss appropriate treatment and referral options with their patients.

An evaluation of a national program to implement the cornell scale for depression in dementia into routine practice in aged care facilities

Background: Screening tools have been recommended for use in aged care to improve the detection and treatment of depression. This study aimed to evaluate the impact of a program for the routine implementation of the Cornell Scale for Depression in Dementia in Australian facilities, to determine whether use of the instrument by nurses led to further monitoring of depressive symptoms, medical referral, and changes in treatments prescribed for depression.
Methods: A file review was completed for 412 participants out of a total of 867 older people (47.5%) who resided in ten aged care facilities. The review examined Cornell Scale assessment data, medication charts, medical history, nursing progress notes, and resident care plans. Nursing staff who administered the Cornell Scale to each participant were also interviewed, and ten facilitymanagers took part in an interview to determine barriers to the effective implementation of the instrument.
Results: The Cornell Scale had been administered to 46.8% of the sample in the previous 12 months, with 25% of these participants scoring 9–13 and 27% scoring 14 and above. Less than one third of the residents with high scores were monitored by the staff following the assessment. Only 18% of residents with high scores were referred for further assessment of depression, while 10% received a treatment change.
Conclusions: The absence of a protocol for responding to high Cornell Scale scores limited the potential of this program to result in widespread improved treatment of depressed older people. The use of the Cornell Scale by aged care nurses with limited training raised concern.

Illness burden and medical comorbidity in the systematic treatment enhancement program for bipolar disorder

Objective:  Coexisting chronic medical conditions are common in bipolar disorder. Here, we report the prevalence and correlates of medical comorbidity in patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). We were particularly interested in associations between variables reflecting illness chronicity and burden with comorbid medical conditions.

Method:  We used intake data from the open-label component of the STEP-BD. History of medical comorbidity was obtained from the affective disorders evaluation, and its presence was the outcome of interest. The sample size in analyses varied from 3399 to 3534. We used multiple Poisson regression to obtain prevalence ratios.

Results:  The prevalence of any medical comorbidity in the sample was 58.8%. In addition to demographic variable, several clinical characteristics were associated with the frequency of medical comorbidity. Having more than 10 previous mood episodes, childhood onset, smoking, lifetime comorbidity with anxiety, and substance use disorders were independently associated with having a medical comorbidity in the final multivariate model.

Conclusion:  The results presented here reveal strong associations between variables related to illness chronicity and medical burden in bipolar disorder. This lends further support to recent multidimensional models incorporating medical morbidity as a core feature of bipolar disorder.

New drug targets in depression : inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

A proof of concept for using brief Dialectical Behavior Therapy as a treatment for problem gambling

Fourteen ‘treatment resistant’ problem gamblers received 9 weeks of Dialectical Behavior Therapy (DBT) at specialist problem gambling services delivered in Melbourne, Australia. This study is the first to investigate the effectiveness of a brief DBT treatment for problem gambling, with a focus on measuring change in the four DBT process skills (mindfulness, distress tolerance, emotion dysregulation, and negative relationships). Although there were no statistically significant improvements in measures of gambling behaviour, 83% of participants were abstinent or reduced their gambling expenditure pre- to post-treatment. Participants also reported statistically and clinically significant improvements in psychological distress,  mindfulness, and distress tolerance. Moreover, there were no increases in alcohol or substance use. These results are discussed in the context of focusing on a single DBT process skill, and the benefits of using group-based approaches.

Staff-focused interventions to increase referrals for depression in aged care facilities: a cluster randomized controlled trial

Objective: 

Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

A case study illustrating therapist-assisted internet cognitive behavior therapy for depression

Randomized controlled trials show that therapist-assisted Internet cognitive behavior therapy (ICBT) is efficacious in the treatment of depression. Given that this is a novel way of delivering cognitive behavior therapy, however, clinical service providers may have questions about how to provide therapist-assisted ICBT in clinical practice, particularly with respect to therapist assistance. To exemplify this approach, we present a case study of an older adult male who received 12 modules of therapist-assisted ICBT for depression over the course of 5. months. Highlights of the therapeutic exchanges that occurred over email are provided to illustrate the type of information clients may share with therapists and the nature of therapist assistance. Treatment progress was assessed via self-report questionnaires measuring depression, anxiety, and adjustment. Consistent with the research evidence, significant improvement was observed on all symptom measures at posttreatment. Satisfaction with the therapist-assisted ICBT program and a strong therapeutic alliance was also reported. The case will expand clinician understanding of therapist-assisted ICBT and may serve to stimulate clinician interest in the provision of therapist-assisted ICBT. Future research directions stemming from this case are presented. © 2013 .