Prediction of the therapeutic response in the treatment of affective disorders using repetitive transcranial magnetic stimulation MUDr. Jakub Albrecht Summary Background: Transcranial magnetic stimulation (TMS) is an effective and safe neuromodulatory treatment of several neuropsychiatric conditions. Treatment resistant depression (TRD) is becoming the leading cause of morbidity and mortality. The design was narutallistic and observational. Methods: The cohort (2016-2018) contains 39 depressed patients (STAR*D grade ≥3). The parameters of TMS were: 10 days of 10 Hz stimulation with an energy of 100 % of motor evoked potential (MEP), 1500 pulses in 15 trains over the left dorsolateral prefrontal cortex. Self-reporting scales were administered prior to and after the final stimulation: Zung's Self-Rating Depression Scale (SDS), Perceived Stress Scale (PSS), Beck's Anxiety Inventory (BAI) and Quick Inventory of Depressive Symptomatology (QIDS-SR). Co-medication was not altered. Results: The subjective effect was significant and widespread with a median decrease: in SDS of 10 points (from 75 ±8.16 to 65 ±9.56), 59 % of patients improved ≥10 % from the baseline; in PSS of 4 points (29 ±5.34 to 25 ±5.90), 62 % improved ≥10 %; in BAI of 4 points (46 ±13.72 to 42 ±11.51), 54 % improved ≥10 %; in QIDS-SR 6 points (17...

Inledning: Depression är ett globalt folkhälsoproblem som drabbar människor i alla åldrar oavsett kön. En tredjedel av alla patienter diagnostiserade med depression blir inte hjälpta av dagens behandlingsmetoder och i synnerhet läkemedel. Denna grupp av individer klassificeras som behandlingsresistenta. För individer som lever med behandlingsresistent depression (TRD) är situationen allvarlig. Suicidala tankar (SI) och beteenden är vanligt förekommande och ökar i takt med svårighetsgraden av depressionen. Upptäckten av ketamins snabba effekter mot depression under 2000-talet har givit nytt ljus åt forskningen och mycket forskning görs på området som indikerar på positiva effekter mot TRD och de suicidala benägenheterna. Ketamin är dock ett problematiskt läkemedel med svåra biverkningar som gör situationen mer komplex. Syfte: Syftet med detta litteraturarbete var att undersöka effekterna av intravenöst (iv) ketamin mot TRD och i synnerhet dess antisuicidala effekter. Metod: Fem kliniska studier har analyserats. Två databassökningar gjordes via databasen PubMed med sökorden ”TRD suicidal ideation ketamine infusion treatment” och ” treatment resistant depression ketamine suicidal cognition”. Inkluderade artiklar valdes utifrån fastställda inklusions- och exklusionskriterier. Resultat: Överlag påvisas ett positivt resultat av ketamins antisuicidala effekter vid TRD. Fyra av fem studier visade signifikanta resultat av en singeldos ketamin jämfört med placebo och en studie kunde visa positiva effekter av upprepade infusioner. Medan en studies resultat varken kunde påvisa positiva effekter på kort eller lång sikt. Diskussion: Sammanfattningsvis indikerar resultatet av inkluderade studier på att ketamin i viss grad har positiva effekter på SI vid TRD och att iv ketamin har potential som läkemedel för denna patientgrupp. Dock krävs det mer forskning kring effektens hållbarhet, långtidseffekter, biverkningar och beroenderisken av ketamin. Idag används ketamin i form av det intranasala läkemedlet Spravato mot svår depression, detta med försiktighet på grund av de allvarliga biverkningar som kan följa och dess okända långtidseffekter. / Introduction: Depression is a global public health problem that affects people of all ages regardless of gender. One third of all patients diagnosed with depression are not helped by today's treatment methods. This group of individuals is classified as the treatment resistant. For individuals living with treatment-resistant depression (TRD), the situation is dire. Suicidal thoughts (SI) and behaviors are common and increase with the severity of the depression. The discovery of ketamine's rapid effects against depression in the 21st century has given new light to research and much research are being done in the area that indicates positive effects against TRD and the suicidal tendencies. However, ketamine is a problematic drug with severe side effects that make the situation more complex. Aim: The aim of this review was to investigate the effects of intravenous (iv) ketamine against TRD and in particular its anti-suicidal effects. Method: Five clinical studies have been analyzed. Two database searches were made via the PubMed database with the keywords "TRD suicidal ideation ketamine infusion treatment" and "treatment resistant depression ketamine suicidal cognition". Included articles were selected based on established inclusion and exclusion criteria. Results: Overall, a positive result of ketamine's anti-suicidal effects in TRD is demonstrated. Four out of five studies showed significant results of a single dose of ketamine compared to placebo and one study was able to show positive effects of repeated infusions. While the results of one study could not demonstrate positive effects in the short or long term. Discussion: In summary, the results of included studies indicate that ketamine has, to some extent, positive effects on SI in TRD and that iv ketamine has potential as a drug for this patient group. However, more research is needed concerningdurability of the effect, long-term effects, side effects and the risk of addiction to ketamine. Today, ketamine is used in the form of the intranasal drug Spravato against severe depression, this with caution because of the serious side effects that can follow and its unknown long-term effects.

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

Depression är ett syndrom som drabbar mer än 300 miljoner människor i världen. Tillståndet förekommer i individuella variationer men vanliga symtom är nedstämdhet, energiförlust, störningar av sömn och aptit samt känslor av skuld och skam. En svår depression kan innebära lidande och stor funktionsförlust för den drabbade. Idag används både psykologisk och farmakologisk behandling, men det finns en problematik kring att det kan dröja veckor eller månader innan klinisk effekt ses av antidepressiva läkemedel. Därutöver blir en tredjedel av patienterna inte tillräckligt hjälpta av den behandling som finns att tillgå. Detta brukar kallas terapiresistent depression (TRD) och är för närvarande svårbehandat. Ketamin är ett narkotikaklassat läkemedel som används för induktion och underhåll av anestesi men som även förekommer som missbruksdrog. Fynd har visat att engångstillförsel av ketamin eventuellt kan ge en snabb antidepressiv effekt hos patienter med TRD. Ketamin är för närvarande inte godkänt för indikationen depression i Sverige. Syftet med denna litteraturstudie var att utvärdera om ketamin har effekt mot TRD. Fem randomiserade kontrollerade studier som hämtats ur databasen PubMed användes. I tre studier undersöktes intravenös tillförsel av ketamin varav en gav upprepade doser, en studie undersökte intravenöst esketamin i varierande doser och en studie undersökte effekten av intranasalt ketamin. Sammantaget visar resultatet att ketamin har effekt mot terapiresistent depression. Efter 24 timmar kunde statistiskt signifikanta skillnader avseende depressionens svårighetsgrad observeras hos de som fått ketamin jämfört med placebo (p &lt;0,05). Ketamin gav 7–16 poängs större reduktion av depressiva symtom än placebo enligt använd skattningsskala, vilket motsvarade en genomsnittlig förändring från svår/medelsvår depression till mild depression. Resultatet visade även statistiskt signifikanta skillnader avseende behandlingsrespons (minst 50 % reduktion av symtompoäng på använd skattningsskala) efter 24 timmar (p &lt;0,05). Andelen patienter med respons varierade mellan 44–71 % jämfört med 0–6 % för placebo och 28 % för aktiv placebo (midazolam). Även om resultatet från aktuella studier verkar lovande för ketamin som antidepressiv behandling krävs ytterligare studier på långtidseffekter och säkerhet vid upprepad tillförsel i en större studiepopulation. / Depression is a syndrome characterized by depressed mood, loss of interest and energy, feelings of guilt or worthlessness and thoughts of death and suicide. Over 300 million people suffer from depression and it is one of the leading causes of disability in the world. Today’s treatment for depression includes psychological treatment as well as pharmacological treatment. While there are many antidepressant drugs, it can take up to weeks or even months before a clinical effect in the severity of the depression can be noticed. In addition, one third of the patients do not achieve remission. These patients, after treatment with two antidepressant medications given at adequate doses for an adequate duration, are considered to have treatment-resistant depression (TRD). Ketamine is a drug long used for its anesthetic and analgesic effects, but it is also known as a party-drug that can cause out-of-body experience. However, it has also been found that a single-dose ketamine may give people with TRD a rapid antidepressant effect, within 24 hours. In contrast to current antidepressant medications which primarily acts on the monoaminergic system, ketamine instead acts on the glutamatergic system. The aim of this study was to evaluate if ketamine has an effect on people suffering from TRD. This study is a literature review where five randomized controlled trials on the effect of ketamine in patients with TRD have been analyzed. Four studies evaluated the effect of intravenous ketamine where one of them used a varied dose frequency and one of them used esketamine in various doses. The fifth study evaluated the effect of intranasal administration of ketamine. All studies were found in the database PubMed. The overall result shows that ketamine has an effect on TRD. After 24 hours all the studies showed a significant improvement in the severity of the depression with ketamine treatment compared to placebo (p &lt;0.05). Ketamine treatment resulted in a 7-16 points larger reduction in depressive symptoms on the scales used compared to placebo. This represents on average a change from severe/moderately severe depression to mild depression. There was also a significant difference in response (at least 50 % reduction in points from baseline on the scale used) after 24 hours with ketamine treatment compared to placebo (p &lt;0.05). The proportion of ketamine treated patients with response varied between 44-71 % compared to 0-6 % for placebo and 28 % for active placebo (midazolam). Even though ketamine seems to have an effect on patients with TRD there is still limited knowledge of how the antidepressant effect shall be maintained and the safety of long-term use. Further studies are needed to determine if ketamine will be an option in future antidepressant treatment against TRD.

Un contenu visuel flou peut-il être efficace pour traiter de l’information émotionnelle ? Récemment, les travaux psychologiques en traitement émotionnel de l’information visuelle font état d’un lien particulier avec l’information de basses fréquences spatiales (BFS), grossière et floue mais rapide, qui permettrait la transmission très rapide de signaux au système émotionnel par rapport à une information de hautes fréquences spatiales (HFS) plus complexe et détaillée. En outre, l’information BFS serait primordiale dans la détection d’un danger potentiel de l’environnement et par conséquent envers des émotions à valence négative. Ces deux types d’informations visuelles emprunteraient des voies neuronales différentes conduisant à une segmentation de cette information visuelle dans le cerveau. Au niveau psychopathologique, des troubles neurologiques comme la maladie de Gilles de la Tourette ou encore la dépression majeure résistante sont connues pour entraîner un déficit des interactions sociales pour lesquelles les traitements émotionnels sont indispensables. Les dysfonctionnements neurologiques et psychobiologiques accompagnant ces troubles impliquent des structures spécifiques et localisées en périphéries ou enfouies dans le cerveau liées à la dichotomie fonctionnelle de l’information visuelle. Un des moyens simples pour appréhender ces traitements est la catégorisation des visages émotionnels. Cette recherche a examiné au niveau théorique et appliqué dans quelle mesure l’information visuelle autrement appelée la résolution en fréquences spatiales (FS) jouerait un rôle dans la catégorisation des expressions faciales émotionnelles (EFEs). Ainsi tant au niveau de la détection visuelle de danger qu’au niveau de l’identification des EFEs dans la maladie Gilles de la Tourette et dans la dépression majeure résistante, nous avons étudié les réponses comportementales dans les premières étapes de décryptage de l’information visuelle convoyant des indices émotionnels. Une comparaison avec une population contrôle a permis de cerner plus précisément les effets d’un filtrage en FS dans les processus de catégorisation avec la prédiction d’un bénéfice à traiter des contenus flous (BFS) par rapport à des contenus détaillés (HFS) pour des EFEs problématiques à classer en fonction de la pathologie. Nos résultats ont suggéré une meilleure identification de certaines EFEs filtrées en BFS par rapport à celles filtrées en HFS ou résolues. Nos données empiriques ont été discutées dans la perspective d’une segmentation de l’information visuelle dans le cerveau sollicitant des circuits neuronaux spécifiques favorisant l’accès de l’information visuelle aux centres émotionnels. En regard des structures cérébrales impliquées et des activités neuronales connus dans les troubles étudiées, l’activité dopaminergique des neurones sollicités pourraient expliquées en partie nos données factuelles. / What can be the efficiency of coarse scales in emotional information processing? Recently, psychological findings about emotional processing of visual information reported a particular link with low spatial frequencies (LSF), coarse and blurred but rapid, which might offer a very fast signal to emotional system compared to high spatial frequencies (HSF) more intricate and detailed. Plus, LSF information might be essential in danger detection and consequently in negative emotions classification. These two types of visual information would take different neural pathways driving to visual information segmentation in the brain. In psychopathological view, neurological disorders as Tourette syndrome or treatment-resistant depression are well known to produce social interaction troubles in which emotions are obligatory. Neurological and psychobiological dysfunctions belonging to these diseases implicate specific neural structures located at peripheral or inside the brain that are bind to functional dichotomy of visual information. One of the simplest ways to examine that processing is the categorization of emotion faces. This research has investigated according to theoretical and practical aspects the extent to which visual information or spatial frequency scaling (SF) might be implicated in categorization of emotional facial expressions (EFE). Thus, both in danger detection and EFE classification, among Tourette syndrome and treatment-resistant depression, we have studied behavioural responses during the first steps of visual information interpretation providing emotional cues. A comparison with healthy control population has given more precise effects of FS filtering in categorization processing with the hypothesis of a benefice to process coarse scales (LSF) compared to detailed signals (HSF) for the identification of difficult EFE in respect with the disorder. Our results have suggested a best identification of specific EFE filtered in LFS compared to HSF or intact images called broad spatial frequencies (BSF). Our empirical findings were argued in the perspective of visual information segmentation in the brain requesting specific neuronal circuits favouring visual information access to emotional complex. Given implicated brain areas and neuronal activities regarding studied disorders, dopaminergic innervation might explain our factual data.

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Environ 30% des patients ne répondent pas de manière adéquate à un traitement antidépresseur. Cette absence de rémission, voire aggravation de l’état dépressif après la mise en place du traitement est qualifiée de non-réponse au traitement. La résistance au traitement est caractérisée lorsque cet échec thérapeutique est récurrent pour différentes stratégies thérapeutiques de mécanisme d’action différents. Afin d’améliorer les stratégies thérapeutiques visant à traiter les patients résistants, une meilleure compréhension des mécanismes biologiques associés à la non-réponse/résistance est nécessaire. De nombreux travaux ont associé le phénomène de neurogenèse hippocampique adulte à la réponse antidépressive, et ont montré qu’un blocage de la neurogenèse altère la réponse antidépressive chez la Souris. Cependant, aucune étude n’a montré si la non-réponse/résistance au traitement était associée à des altérations de la neurogenèse. De plus, il n’existe à ce jour aucun modèle de résistance qui ne présente une validité translationelle à ce qui est observé chez l’Homme. Enfin, alors que 2/3 des patients dépressifs sont des femmes, la majorité des études précliniques sont réalisées chez des mâles. Le but de mon travail de thèse a donc été de modéliser la résistance au traitement antidépresseur chez la souris C57BL6 mâle et femelle.Le premier objectif de ce travail a été la modélisation chez la femelle d’un phénotype anxio-dépressif, en adaptant un modèle neuroendocrinien de la dépression élaboré chez le mâle, basée sur l’administration chronique de corticostérone. Le deuxième objectif a été l’étude de la comparaison de la neurogenèse entre les souris répondeuses et non-répondeuses à un traitement chronique de fluoxétine ou résistantes à 2 stratégies successives de traitement présentant un mécanisme d’action différent (fluoxétine puis imipramine).D’autre part, les données de la littérature clinique suggèrent qu’un marqueur périphérique, la protéine β-arrestine 1, serait un marqueur de l’état dépressif et de la réponse au traitement. Nous avons donc mesuré dans notre modèle les variations de ce potentiel biomarqueur clinique.L’ensemble de ces travaux de thèse a permis de montrer la complexité d’induire un phénotype anxio/dépressif chez la souris femelle de façon stable et robuste via l’administration chronique de corticostérone. Chez le mâle, nous avons pu modéliser la résistance au traitement antidépresseur dans le modèle CORT. Nous avons pu observer que les processus neurogéniques semblent jouer un rôle essentiel dans la réponse au traitement, puisqu’une absence de réponse est associée avec une altération de la neurogenèse hippocampique adulte. Si dans notre modèle, l’expression périphérique de la β-arrestine 1 n’est pas diminuée chez les souris présentant un phénotype anxio-dépressif, elle permet cependant de discriminer les souris répondeuses des souris résistantes au traitement, ce qui valide son intérêt en tant que biomarqueur de la réponse antidépressive. / Around 30% of patients do not respond adequately to chronic antidepressant treatments. This lack of response, or worsening of the depressive state after the onset of the treatment can lead to treatment resistant depression (TRD). TRD is characterized by a recurrent lack of therapeutic response to various antidepressant which display different mechanism of action. A better understanding of the mechanisms that underlies TRD is necessary to discover some new effective therapeutic strategies. Numerous studies in rodents have shown that chronic antidepressant treatment improves adult hippocampal neurogenesis, and that disrupting this phenomenon partially alters antidepressant response. However whether lack of response or resistance to antidepressant treatment is associated with altered neurogenesis has yet not been observed. Additionally, there is yet no model of TRD with a translational validity. As major depressive disorders affects women twice more than men, yet the preclinical studies are performed mostly in males. Thus, the aim of this thesis was to model non-response an resistance to antidepressant response in male and female C57BL6 mice.The first aim of this thesis work was to induce a anxio-depressive phenotype in female mice, by adapting a neurodencocrine model of depression developed in males and based on chronic administration of corticosterone (CORT). The second aim was to study adult hippocampal neurogenesis in animals that respond or not to chronic fluoxetine administration, and in animals that were resistant to two successive antidepressant treatment with a different mechanism of action (fluoxetine and then imipramine).Additionally, data from the literature suggests that peripheral β-arrestin 1 expression could be a potential biomarker of depressive state and antidepressant response in humans. Thus, we explore its validity in our model of TRD in mice.Overall, our results highlight the difficulty of inducing an anxio-depressive phenotype in female mice, using different dosage or treatment duration of corticosterone, which hampers the use of corticosterone to induce emotionality in female mice.However, in male mice, we showed that we were able model resistance to treatment in the using the CORT model. Lack of response to chronic fluoxetine and treatment resistance to fluoxetine/imipramine were associated with altered neurogenesis in the dentate gyrus of the hippocampus. This confirms that hippocampal neurogenesis is critical for a full antidepressant response. While peripheral β-arrestin 1 expression was not decreased after chronic CORT exposure, its differential expression between responder vs treatment-resistant mice confirms its validity as a biomarker for antidepressant response.

Background: Nonresponsiveness to therapy is generally acknowledged, but only a few studies have tested switching to psychotherapy. This study is one of the first to examine the malleability of treatment-resistant patients using acceptance and commitment therapy (ACT). Methods: This was a randomized controlled trial that included 43 patients diagnosed with primary panic disorder and/or agoraphobia (PD/A) with prior unsuccessful state-of-the-art treatment (mean number of previous sessions = 42.2). Patients were treated with an ACT manual administered by novice therapists and followed up for 6 months. They were randomized to immediate treatment (n = 33) or a 4-week waiting list (n = 10) with delayed treatment (n = 8). Treatment consisted of eight sessions, implemented twice weekly over 4 weeks. Primary outcomes were measured with the Panic and Agoraphobia Scale (PAS), the Clinical Global Impression (CGI), and the Mobility Inventory (MI). Results: At post-treatment, patients who received ACT reported significantly more improvements on the PAS and CGI (d = 0.72 and 0.89, respectively) than those who were on the waiting list, while improvement on the MI (d = 0.50) was nearly significant. Secondary outcomes were consistent with ACT theory. Follow-up assessments indicated a stable and continued improvement after treatment. The dropout rate was low (9%). Conclusions: Despite a clinically challenging sample and brief treatment administered by novice therapists, patients who received ACT reported significantly greater changes in functioning and symptomatology than those on the waiting list, with medium-to-large effect sizes that were maintained for at least 6 months. These proof-ofprinciple data suggest that ACT is a viable treatment option for treatment-resistant PD/A patients. Further work on switching to psychotherapy for nonresponders is clearly needed.

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.