[Treatment resistant depression: actuality and perspectives in 2017]. / Dépression résistante au traitement : actualité et perspective en 2017.

Major depressive disorder (MDD) affects 3 to 17 % of adults. 15 to 30 % of patients with MDD suffer from treatment resistant depression (TRD). No international consensus defines TRD. The most common definition is " MDD that is not enough improved after two successive and different classes of antidepressant treatments in appropriate dose and duration ". The appropriate dose corresponds to maximal dose accepted by scientific reports and clinical recommendations, while the appropriate duration is around 6 weeks. TRD is diagnosed after excluding a pseudoresistant depression, that is related to weak compliance or to somatic and psychiatric differential diagnosis. As well as in MDD, molecular, neuro-anatomical and metabolic disturbances are involved in TRD. A decreased cerebral plasticity induced by low level of Brain-Derived Neurotrophic Factor (BDNF) is also reported. Several authors describe that the cerebral atrophy and the dopaminoglutaminergic system disturbances are more severe in TRD than in MDD. In contrast to MDD treatment, TRD treatment is most often physical treatment. Electroconvulsive therapy (ECT) followed by a tricyclic antidepressant and/or lithium is the most effective treatment. Deep brain stimulation and vagal nerve stimulation reach also a high rate of remission but they are both very invasive technique. Repetitive transcranial magnetic stimulation in TRD seems to be effective in TRD but lower than ECT. There are two majors purposes for this review. First it may help the clinician to understand the TRD's complexity and also it details the kind of treatment useful to care it.

3 à 17 % de la population adulte souffre d'un épisode dépressif majeur (EDM). Parmi ceux-ci, 15 à 30 % présenteront une dépression résistante au traitement (DRT). Malgré l'absence de consensus international sur une définition de la DRT, la définition la plus fréquemment utilisée est " l'EDM est caractérisé par l'absence d'effet acceptable après deux traitements médicamenteux antidépresseurs de classes différentes prescrits à dose et durée adéquates ". La dose adéquate est reconnue comme la dose maximale autorisée par les recommandations officielles ; tandis que la durée adéquate, basée sur un ensemble d'études pharmacologiques contrôlées et randomisées, varie souvent autour de 6 semaines. Le diagnostic de DRT peut être posé après avoir exclu toutes causes de pseudorésistance : soit une mauvaise compliance au traitement, soit la présence d'un autre diagnostic différentiel psychiatrique ou somatique. Tout comme dans l'EDM, des perturbations moléculaires, neuro-anatomiques et métaboliques sont également en cause dans la DRT. Une diminution de la plasticité cérébrale provoquée par une diminution du facteur de croissance Brain-Derived Neurotrophic Factor (BDNF) est également rapportée. Plusieurs auteurs décrivent une atrophie cérébrale plus importante et un plus grand dysfonctionnement des systèmes dopamino-glutaminergiques chez les patients souffrant de DRT. Le traitement des DRT est essentiellement basé sur les techniques de neurostimulation. L'électroconvulsivothérapie (ECT) avec relais vers un antidépresseur tricyclique et/ou le lithium reste le plus efficace. La stimulation cérébrale profonde et la stimulation du nerf vague présentent également des taux de rémission élevés mais restent des techniques invasives. La stimulation magnétique trans-crânienne répétitive apporte également de bons résultats en cas de DRT. Toutefois son efficacité reste inférieure à celle de ECT. Le but de cet article est double : aider le clinicien à comprendre la complexité de la DRT, et offrir une revue détaillée des différents traitements, pharmacologiques ou non, pouvant y faire face.

[Support for insomnia : Recommendations for practice in general medicine]. / Prise en charge de l'insomnie : Recommandations pour la pratique en médecine générale.

In Belgium, poor sleep complaints are numerous and frequent in the general population. Of these complaints, one of the most important is insomnia. Acute onset and chronicity of insomnia can be explained by different models based on genetic criteria, neurophysiological, neuroendocrine, neuroimmunological and neuroimaging. Insomnia can be associated with a lot of somatic and psychiatric comorbidities. The diagnosis of insomnia is primarily a clinical diagnosis based on medical history and physical examination. Different tools can help us in our approach, such as self-questionnaires and sleep diaries while additional tests (polysomnography and actigraphy) should be reserved for research of associated sleep disorders and for unclear situations. The management of insomnia can be non-drug treatment (exercise, light therapy, acupuncture and self-treatment cognitive behavioral therapy) but also drug treatment (benzodiazepine, Z-DRUGS, melatonin, antidepressants, herbal medicines, neuroleptics and antihistaminics). Each of these approaches has advantages and disadvantages that must be considered when choosing treatment. The aim of this review is to allow general practitioners to better understand the mechanisms of insomnia and to have recommendations for the diagnosis and treatment of insomnia.

En Belgique, les plaintes de mauvais sommeil sont multiples et fréquentes dans la population générale. Parmi ces plaintes, l'une des plus importantes est l'insomnie. La survenue aiguë et le passage à la chronicité de l'insomnie peuvent être expliqués par différents modèles reposant sur des critères génétiques, neurophysiologiques, neuroendocriniens, neuroimmunologiques et de neuroimageries. L'insomnie peut être associée à de nombreuses comorbidités somatiques et psychiatriques. Le diagnostic de l'insomnie est avant tout un diagnostic clinique reposant sur l'anamnèse médicale et l 'examen physique. Différents outils peuvent nous aider dans notre démarche, tels que les auto-questionnaires et les agendas de sommeil tandis que les examens complémentaires (polysomnographie et actimétrie) sont à réserver à la recherche de pathologies du sommeil associées et pour les situations peu claires. La prise en charge de l'insomnie peut être non médicamenteuse (exercice physique, luminothérapie, acupuncture, auto-traitement et thérapie cognitivocomportementale), mais aussi médicamenteuse (benzodiazépines, Z-DRUGS, mélatonine, antidépresseurs, médicaments à base de plantes, neuroleptiques et antihistaminiques). Chacune de ses approches présente des avantages et des inconvénients dont il faudra tenir compte lors du choix du traitement. Le but de cette revue est de permettre aux médecins généralistes de mieux comprendre les mécanismes de l'insomnie et de disposer de recommandations pour le diagnostic et le traitement de l'insomnie.

[Influence of depressive history on biological parameters in major depression]. / Influence de l'histoire dépressive sur les paramètres biologiques dans la dépression majeure.

BACKGROUND: Major depressive disorder is associated with several biological abnormalities. Among them, sleep disturbances and alterations of hypothalamic structures and cortisol system have been largely studied. Most studies have found a relationship between depression and alteration of sleep. Electroencephalic sleep profiles during depression demonstrate abnormalities of sleep continuity, reduction of slow waves sleep and REM pressure (27). The cortisol system, investigated by the Dexamethasone Suppression Test (DST), is abnormal in about an half of the depressed subjects. We confirm a cortisol escape from suppression by dexamethasone (21). A complex dysregulation of the Hypothalamic Pituitary Adrenal axis (HPA) is thought to explain this escape (15, 33). The HPA has been first involved in the theory of stress. There are two ways to study this. First by looking at early adversities and genetic susceptibility to stress, and second by studying acute stressors and depressive reactions (8). The sensitization model postulated that the acute abnormalities of depression may leave biological scares. Those scares could make people more vulnerable to latter depressive triggers (34). We could then suppose that biological correlates of depression become more severe during the course of the illness. The present study further examines relationships between DST, polysomnography and some clinical and epidemiological characteristics of the depressive illness. We tried to examine if there were increasing biological disturbances during the course of the illness. We also examined the effect of the history of illness on the psychosocial stressors, and the effects of those stressors on the biological correlates of depression. METHODS: The DST and polysomnographic recordings were performed in a sample of 130 inpatients with primary major depressive disorder, unipolar form, as defined with the RDC (41). All of those patients have been consecutively admitted to the Sleep Laboratory of the Department of Psychiatry, Erasme Hospital, between 1981 and 1992. This population has been previously reported elsewhere (19, 20, 21). The depressive symptom severity was assessed with the 24-items HRSD (17). The Newcastle Endogenous Depression Diagnostic Index was used to assess the endogenous character of the depressive episode (5). The history of the illness and the impact of psychosocial stressors were assessed retrospectively using the interview associated with the RDC (41), the SADS (7). Psychosocial stressor has been assessed using the item 216 of the SADS. We must remind that it is not a precise measurement of stress. RESULTS: Table I shows clinical characteristics and biological variables in our 130 depressed patients. No correlation were found between number of depressive episodes and DST or EEG sleep records (table II). Age of onset was correlated with DST and all sleep EEG parameters (REM latency, REM density, awakening and slow wave sleep). But the age was a major confounding factor. When corrected the results for age, a significant correlation between age of onset and DST still remained, but no correlation between age of onset and EEG sleep results (table III). The psychosocial stressors were correlated only with awakening. A positive trend was found between an augmentation of psychosocial stressors and the number of episodes (p = 0.06). CONCLUSION: This study does not support the view that the biological correlates of depression are worsening with the course of the illness. We found only correlation between age of onset and DST, but a possible confounding effect of age cannot formerly be excluded. The impact of psychosocial stressors on the biological correlates of depression was minimal. The only significant correlation found was between awakening and psychosocial stressors. We found no correlation between psychosocial stressors and the course of depression. Those results do not support the view of sensitization of the illness, but it should be remember that evaluation of psychosocial stressors by item 216 of the SADS was probably not a sufficient sensitive measure. We suggest thus that the impact of the history of depression on biological correlates of depression is not very strong. An alternative explanation of the lack of correlation found is that we used inaccurate measurement of the course of depression. For example, we had no evaluation of the quality of remission between different episodes of depression and of subsyndromic depression. Recent works show the importance of this (6, 9). The major limitations of this work were the retrospective character of the study and the low precision of the evaluation of psychosocial stressors used.

Shortened REM latency as a psychobiological marker for psychotic depression? An age-, gender-, and polarity-controlled study.

BACKGROUND: Previous reports suggest that the clinical dichotomy separating psychotic and nonpsychotic depression corresponds to different neurobiological profiles. The aim of the present study is to further investigate the psychobiological correlates of these two particular depressive subtypes. METHODS: Thyroid-stimulating hormone response to thyrotropin-releasing hormone postdexamethasone cortisol levels, and electroencephalgraphic sleep characteristics of 44 psychotic major depressive patients were compared to those of 44 nonpsychotic depressives matched for age, gender, and polarity. RESULTS: Some biological disturbances usually associated with depression (increased wakefulness, diminished rapid eye movement latency, hypercortisolism, blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation) seemed to be significantly more pronounced in the psychotic depressed group as a reflection of greater illness severity; however, shortened REM latency was not influenced by severity and seemed to be more specifically related to the co-occurrence of psychotic and depressive symptoms. CONCLUSIONS: Our data provide further support for the validity of the clinical dichotomy separating psychotic and nonpsychotic major depression independently of severity.

Neuroendocrine and clinical characteristics of major depressed patients exhibiting sleep-onset REM.

BACKGROUND: Previous reports suggest an association between sleep-onset REM (SOREM) and some clinical characteristics in depressive illness such as age, psychosis, and depression severity. The present study is aimed at further investigating clinical and neuroendocrine correlates of SOREM, controlling for the age-related variability in clinical data. METHODS: Thyroid-stimulating hormone response to thyrotropin-releasing hormone, postdexamethasone cortisol levels, and clinical characteristics of 25 major depressive (MD) patients exhibiting SOREM in at least one of three consecutive recording nights were compared to those of 25 age- and sex-matched MD patients with three REM latencies above 50 min. RESULTS: SOREM patients experienced more affective episodes leading to hospitalization and a shorter duration of current episode than patients with three REM latencies above 50 min. No association between psychosis and SOREM could be demonstrated, and hypothalamic-pituitary-adrenal or -thyroid axis disturbances were not more prevalent in SOREM patients. CONCLUSIONS: Our results suggest that clinical history rather than cross-sectional clinical characteristics relates to the occurrence of SOREM in major depressed patients.

Does sleep EEG data distinguish between UP, BPI or BPII major depressions? An age and gender controlled study.

Clinical characteristics and sleep EEG data of 14 unipolar (UPR), 14 bipolar I (BPI) and 14 bipolar II (BPII) patients, matched for age and gender, were investigated during a major depressive episode. We observed a remarkable similarity in the clinical characteristics of the three samples and, concerning sleep EEG data, a trend to a higher percentage of awakening among BPI patients. Pairwise comparisons of the three subgroups showed that only the Newcastle rating scale score reached significant difference between BPI and UPR groups. We observed trends regarding the difference of awakening both between BPI and BPII groups and between BPI and UPR groups, difference of percentage of REM sleep between BPI and BPII groups and difference of Sleep Period Time between BPII and UPR groups. We also observed that the distribution of REM latencies in the BPI subgroup was different from the two others.

The dexamethasone suppression test and sleep electroencephalogram in nonbipolar major depressed inpatients: a multivariate analysis.

BACKGROUND: The present study further examined relationships between postdexamethasone cortisol plasma values and sleep electroencephalogram (EEG) parameters. METHODS: The dexamethasone suppression test (DST) and polysomnographic recordings were performed in a sample of 300 inpatients with primary major depressive disorder (MDD) (102 men and 198 women, mean age 44 +/- 12 years, range 20-74 years) consecutively admitted to Erasme Hospital (Brussels, Belgium) between 1981 and 1992. RESULTS: The DST was abnormal in 40% of the sample. Postdexamethasone cortisol plasma values at 4:00 PM were significantly influenced by age, but not by gender. They were also significantly and positively correlated with weight loss, total scores on the Hamilton Depression Rating Scale, total scores on the Newcastle Scale, percentage of awakenings during sleep, and percent of stage 1. They were significantly and negatively correlated with percent of stage 2, slow-wave sleep, and REM sleep. Multiple regression analyses were conducted in two successive steps. First among clinical variables, only age and depressive symptom severity remained correlated with postdexamethasone plasma cortisol values. In the second step, with age and severity held constant, postdexamethasone plasma cortisol values were positively associated with amount of wake time and stage 1, and negatively with amount of slow-wave sleep. CONCLUSIONS: These findings provide further indirect support for an overarousal state in MDD with sympathoadrenal system hyperactivity and impaired sleep continuity. They also underline the importance of taking into account various clinical confounding factors in the interpretation of both DST and sleep EEG results.

[Sleep during post-partum depression]. / Le sommeil durant la dépression du post-partum.

BACKGROUND: Numerous studies have been published on postnatal depression (PND) over the last 10 years. A controversy has arisen regarding the specificity of the diagnostic concept. It is based on 2 points: the hormonal environment and the course and recurrence of PND. EEG Sleep studies are also numerous, but this paper presents the first study on EEG sleep profile during PND. METHODS: 24 women suffering from major depression according to RDC were placed in 3 groups: 1) Group A (n = 8): PND; 2) Group B (n = 8): depression with a past history of PND; 3) Group C (n = 8): depression without a past history of PND. Women were age-matched and according to the Hamilton 24 item severity score. Group A patients were delivered within less that 6 months, groups B and C within a minimum of 3 years. None were pregnant or alcoholic, and none were physically ill. RESULTS: There was no difference between groups B and C. Group A was characterised by a significantly longer stage IV sleep. There was also a strong tendency to a shorter stage I sleep and a better quality of sleep (total sleep time and number of awakenings) during PND. DISCUSSION: Our study shows that, even if similar to major depression, specific polysomnographic alteration can be found during post-partum depression. This finding is relevant to the hypothesis of PND's diagnostic specificity. The perfect similarity between groups B and C strengthens this evidence. Nevertheless, the significance of SWS alterations are difficult to explain and additional studies are required. CONCLUSION: The EEG Sleep profile during PND differs from major depression of the same severity. This appears to favour the specificity of the diagnostic concept.

Neuroendocrine and sleep variables in major depressed inpatients: role of severity.

To evaluate the reliability of the endogenous concept of depressive illness according to the Newcastle Endogenous Depression Diagnostic Index (NEDDI), 155 major depressive inpatients with NEDDI scores > or = 6 (endogenous) were matched for gender and age (+/- 5 years) to 155 major depressive inpatients with NEDDI scores < 6 (nonendogenous). When sleep polygraphic variables, neuroendocrine parameters (dexamethasone suppression and thyrotropin-releasing hormone tests), and various clinical variables (unipolar/bipolar status, psychotic/nonpsychotic subtype, and severity of the depressive episode) were examined, statistically significant differences between endogenous and nonendogenous patients emerged for three variables: the thyroid-stimulating hormone response to the thyrotropin-releasing hormone test, the dexamethasone suppression test response at 16:00 h, and the percentage of time awake during the night. However, when the effects of age and severity of depression were controlled, those differences disappeared.

[Sleep disorders and neuroendocrine regulation in depression]. / Anomalies du sommeil et de la regulation neuroendocrinienne dans la depression.

In a series of investigations we explored 24 hour neuroendocrine profiles as well as sleep patterns in a sample of monozygotic and dizygotic normal twins as well as in a group of depressed and schizophrenic patients. Our results indicate that genetic factors influence some sleep variables, mainly the slow wave sleep. They also indicate that a disorder of circadian time-keeping (a phase advance of the biological clock) characterizes some forms of affective illness.

Relationship between the Newcastle scale and sleep polysomnographic variables in major depression: a controlled study.

In order to investigate the reliability of the endogenous concept of depressive illness with some sleep EEG parameters, we studied 39 male inpatients suffering from a nonbipolar major depressive episode (15 endogenous (MDDE) and 24 nonendogenous (MDDNE)) and 20 age and sex matched normal controls (C). All patients were diagnosed according to the Research Diagnostic Criteria (RDC) and the endogenous character of the episode was assessed with the Newcastle Endogenous Depression Diagnostic Index. We found significant differences for the following variables between the three groups (MDDE, MDDNE and C): sleep period time (SPT), REM latency, stage II, slow wave sleep (SWS), REM latency expressed as a continuous variable and REM latency expressed as a dichotomizing variable with a threshold of 50 min. These variables were used to compare the endogenous and the nonendogenous depressed patients and also the major depressed patients and the normal controls. Significant differences were observed between all depressed patients and control subjects for amount of SWS and REM latency which were both reduced in endogenous and nonendogenous depressed patients. No significant difference was observed between endogenous and nonendogenous depressed patients, except for the REM latency expressed with a threshold of 50 min (more frequently observed in endogenous depressed patients). Our data support the observation that SWS and REM latency are decreased in major depressive patients. However, in this age and sex controlled study, subtyping nonbipolar major depressive disorder for an endogenous character by the Newcastle Endogenous Depression Diagnostic Index (NEDDI) did not reveal further significant differences for sleep EEG variables, except for the shortening of the REM latency expressed as a dichotomizing variable.

TSH response to TRH and EEG sleep in non-bipolar major depression: a multivariate approach.

The TSH response to TRH and selected sleep EEG variables were studied in a homogeneous sample of 280 non-bipolar major depressed inpatients (95 males and 185 females). The TSH response to TRH was blunted in 28% of the sample. delta max TSH was correlated negatively with age, Hamilton rating scale, Newcastle scale, percentage of wake, and positively with basal TSH, percentage of stage II, slow wave sleep, REM sleep and REM latency. delta max TSH was also lower in male patients and in patients suffering from an endogenous or a psychotic subtype of major depression. Basal TSH was only correlated negatively with the Newcastle score. In view of intercorrelations between all these variables, and because of the confounding effect of age, gender and severity on both the TSH response to TRH and sleep EEG variables, a multiple regression analysis was performed and demonstrated that basal TSH and gender were the two variables with the highest contribution to the delta max TSH variance, followed by age and the presence of psychotic symptoms. When controlling strictly for these significant effects, correlation with the severity or with the endogenous character of depression, and with sleep EEG parameters disappeared.

Frontal and parietal metabolic disturbances in unipolar depression.

The authors investigated brain glucose utilization using positron emission tomography (PET) in 12 normal volunteers and 12 unipolar unmedicated depressed patients (six endogenous; six nonendogenous) following injection of [18F]fluoro-deoxyglucose (FDG). Compared by analyses of variance, absolute and relative regional glucose metabolic rates appeared different in depressed patients and control subjects, especially in parietal and frontal lobes. In patients with unipolar depression, metabolic rates were increased in the orbital part of the frontal lobe and decreased in a frontal dorsolateral area. The metabolic supero-basal gradient calculated in the frontal cortex was significantly lower in depressed patients than in normal subjects. Decreased glucose metabolism was also observed in the parietal cortex of depressed patients. No differences in glucose metabolic rates have been detected between endogenous and nonendogenous patients. No correlation has been found between the metabolic data and the Hamilton Rating Scale.

The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania.

OBJECTIVE: To characterize sleep and the 24-hour profiles of cortisol, prolactin (PRL), and growth hormone (GH) secretion in mania. METHODS: Blood was sampled at 15-minute intervals, and sleep was polygraphically recorded in eight unmedicated male patients with pure mania and the results compared with those from a group of 14 healthy age-matched controls. The circadian, sleep-related, and pulsatile hormonal variations were quantitatively characterized using specifically designed computer algorithms. RESULTS: The manic state was associated with alterations of corticotropic activity and circadian rhythmicity partially overlapping those previously observed in acute endogenous depression, consisting of an elevation of nocturnal cortisol levels and an early timing of the nadir of the circadian variation. Sleep onset was delayed and the sleep period was reduced. A trend for short rapid eye movement latencies was apparent in the adult patients. Both the amount and the temporal organization of PRL and GH secretion were normal. CONCLUSION: The manic state seems to be characterized by similar but less severe neuroendocrine and circadian abnormalities, compared with major depression.

Circadian and sleep-related endocrine rhythms in schizophrenia.

Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.