Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

Impact of the first wave of the COVID-19 pandemic on French Health students.

CONTEXT: In France, care workers and health students have been intensely mobilized during the first wave of the COVID-19 pandemic. But few studies have evaluated psychological distress on non-medical health students, in addition to the challenges posed by pedagogical continuity while universities are closed following health and safety regulations. OBJECTIVES: This study aims to assess COVID-19's impact on health students in France on different levels: psychological, educational and social. METHODS: An online national cross-sectional study, from April 11 to May 30 2020, included sociodemographic, work conditions and numeric scales. RESULTS: A total of 4411 students answered. Regarding the K6 scale, 39% of students had moderate distress, and 21% had a high level of distress. Risk factors of psychological distress included being a woman (P<0.001), being between 19 and 21 years old (P<0.001), living alone (P=0.008), and not having the ability to isolate (P<0.001). Students on the frontline had less psychological distress (57 vs 62%, P=0.003), better quality of sleep (34% vs 28% high quality, P<0.001) but a higher consumption of medical (8.5% vs 6.5%, P=0.044) and non-medical (18% vs 10%, P<0.001) psychotropic drugs. Nurse and medical students had more distress and used more non-medical psychotropic substances than other health students (15% vs 9.2%). DISCUSSION: COVID-19' crisis had an important impact on health students' mental health, social life and training with discrepancies regarding the speciality whether they were on the frontline or not. There is an urgent need for psychological and pedagogical support for students, and even more so regarding the prolongation of the COVID-19 epidemic.

Racing and crowded thoughts in mood disorders: A data-oriented theoretical reappraisal.

OBJECTIVES: Speed of thought is a central phenomenon in mood disorders. We aimed to provide an update on the topic ten years after a first narrative review published on racing and crowded thoughts in mood disorders. This update is based on recent publications, including recent works of our group. METHODS: Narrative review based on publications from the last ten years including publications of our group and a systematic research of references on PubMed. RESULTS: The traditional dichotomist view of racing versus crowded thoughts is not refuted but appears to be more complex, as revealed by validation studies of the Racing and Crowded Thoughts Questionnaire. Moreover, this dualistic view can no longer be conceptualized in a simple bijective concordance with the distinction of hypomania versus mixed depression. We also show that racing/crowded thoughts are strongly associated with mixed depression and not with non-mixed depression, that they tend to be more associated in hypomania to irritability than to the typical symptoms of energy and activity increase and that they are clearly distinguishable from ruminations. Yet, although tightly linked to mood disorders, racing/crowded thoughts appear to be associated to anxiety as well as attention deficit/hyperactivity disorder and insomnia. CONCLUSIONS: Racing and crowded thoughts should be studied in a dimensional perspective as an important facet of mind activity within and beyond the field of mood disorders.

[IDEM-depression: Characteristics and evaluation of an open group that combines psychoeducation and cognitive-behavior therapy]. / IDEM-dépression : caractéristiques et évaluation d'un groupe ouvert combinant psycho-éducation et thérapie cognitivo-comportementale.

INTRODUCTION: Depression is a highly prevalent mental illness that is associated with high rates of morbidity and functional impairment. At the psychiatric unit of the University Hospital of Strasbourg, France, we have developed an open group that combines psychoeducation and cognitive-behavior therapy (CBT), the information, discovery, exchange and mobilization for depression group (IDEM-depression). IDEM-depression is composed of 17 thematic, structured, and independent sessions, which address different aspects of depression (i.e., rumination, pharmacological treatments). Because of its flexible format, patients with varying degrees of depression severity (from remission up to severe depressive symptoms) and whose depression might be bipolar or unipolar, are able to participate in the group. Thus, the group is well suited to a large number of patients with major depression. In the present study we aimed at describing the IDEM-depression group and presenting results regarding patients' overall satisfaction, assessed via two self-report questionnaires (the Client Satisfaction Questionnaire, the CSQ-8, and the IDEM ad hoc questionnaire), as well as its effect on mood following each session assessed via a visual analog scale (VAS) ranging from 0 up to 100. METHOD: Sixty-five patients participated in 50 sessions of the IDEM-depression group in two hospitals in Alsace. 61% of the patients had bipolar disorder, and 41% of them were inpatients. Sessions took place on a weekly basis, lasted 2hours and were proposed by a CBT-trained clinical psychologist. Patients were asked to fill-out the VAS at the beginning and at the end of each session. Moreover, they were asked to fill-out the CSQ-8 and the IDEM ad hoc questionnaire when they left the group. Other than one session ("yoga and mindfulness"), all the sessions (16 out of 17) were structured on a Powerpoint© presentation. During the first hour information was given regarding the topic (i.e., rumination), and a shared CBT conceptualization of the topic was formulated by the participants and the psychologist. For most sessions, the first hour was therefore communication and information-based, whereas during the second hour participants were asked to participate in in-session behavioral experiments and/or to evaluate specific aspects of their behavior (thoughts, emotions, activity, mindful behavior) during the last few days. The therapist manual and the slides for each session are available via e-mail to the first author. RESULTS: Regarding the results, self-reported mood on the VAS was compared between the onset (225 VAS) and the end (225 VAS) of each session. Overall, results suggest that self-reported mood is significantly improved following the participation in sessions (t=-5. 87, P<0.001). Moreover, mean results on the CSQ-8 suggest that patients are highly satisfied with the group (M=24.46, SD=6.42). Among them, 82% reported a moderate-high satisfaction with the group. On the IDEM ad hoc questionnaire, patients reported an overall high satisfaction level regarding (i) the content of sessions, (ii) the duration of sessions, (iii) the frequency of sessions, (iv) how much they felt they could express themselves during sessions. In the qualitative comments of this questionnaire, patients reported that the group helped them to gain an understanding of the mechanisms involved in depression; to feel less isolated and guilty; and to learn about specific psychotherapeutic tools (i.e., mindfulness) and to try to implement them. CONCLUSION: Our results suggest that an IDEM-depression group is well suited to a wide-array of clinical pictures associated with depression (varying severity, bipolar or unipolar, inpatients and outpatients). This is probably due to its open-group format which is particularly well-adapted to the dynamic symptomatology associated with major depression, and may stimulate decentering in patients who have different levels of severity of symptoms but participate in the same session. Moreover, its impact on mood improvement, and the high satisfaction level reported by patients, seem to be related to its CBT and psychoeducation-based content on the one hand, which has shown its efficacy in depression. On the other hand, IDEM's structured open-group format might have also contributed to the improvement in mood and the overall good satisfaction reported by patients, through the social support provided by the group, improved feeling of self-efficiency, and its effect on stigmatization. Thus, IDEM-depression group is an efficacious, flexible, low-cost, and easy to implement (in different clinical settings) psychotherapeutic option for major depression.

[Mixed depression and DSM-5: A critical review]. / Dépression mixte et DSM-5 : mise au point critique.

BACKGROUND: Mixed depression is a depressive syndrome characterized by the presence, along with the typical depressive symptoms of depression, of those of over activation and excitation. If sometimes this activation is expressed by classical hypomanic symptoms, it is often observed by means of more subtle expression: inner tension, crowded thoughts, dramatic expression suffering, and unproductive agitation. It is important to identify mixed depression because such patients are particularly at risk of suicidal behaviors, substance abuse and therapeutic resistance. Even if therapeutic strategies continue to be discussed, treatments should rely on mood stabilizers and antipsychotics instead of antidepressants as in pure depression. Even though the concept of mixed depression has been described for more than twenty years, first by Koukopoulos and then by other authors, it had been little studied, especially because it did not appear in international psychiatric classifications. The DSM-IV supported a very narrow conception of the mixed states because the criteria required simultaneous full manic and full depressive syndromes, corresponding only to some dysphoric manias. The recently published DSM-5 proposes modifications in mood and bipolar disorder classifications, and especially introduces the possibility to specify depressive and manic episodes with "mixed features". To diagnose depression with mixed features, a full depressive syndrome has to be present together most of time with three hypomanic symptoms, except symptoms that are considered as overlapping (that can be observed either in mania or in depression), i.e. agitation, irritability and distractibility. METHODS: Critical analysis of DSM criteria and review of literature. RESULTS: We first analyzed the clinical relevance of the definition of depression with mixed features which could correspond to mixed depression. The problem is that the hypomanic symptoms allowed by the manual lead to symptom associations that are rather illogical (as euphoria with depression) or improbable (as increased or excessive involvement in activities that have a high potential for painful consequences). Also, some more specific symptoms that can be observed in mixed depression are not mentioned (such as hypersensitivity to light or noise, absence of motor retardation, dramatic expressivity of suffering). The DSM-5, as did DSM-IV, refers to an understanding of mixed depression as a simple addition of depressive and manic symptoms. The classification does not take into account that the symptoms could be rather different from hypomania, as the expression of an overactive thought in a depressed mind. Secondly, we reviewed cohort studies using the DSM-5 criteria (or similar criteria with the exclusion of overlapping symptoms), and as a consequence of the poorly defined symptoms, we found that the diagnosis of mixed depression according to DSM-5 is almost impossible, either in unipolar or in bipolar depression. CONCLUSIONS: We think, with others, that the definition of the mixed depression by the DSM-5 is not clinically relevant and misses important information about the concept. Clinicians can be attentive to the identification of mixed character in depression, even if DSM-5 criteria are not fully met. Unfortunately, the DSM-5 definition could undermine research efforts for a better understanding of epidemiology, phenomenology and therapeutics of mixed depression. We propose and discuss alternative solutions for defining mixed depression, such as the absence of exclusion of "overlapping" symptoms, a more insighted phenomenology, or a dimensional approach.

[Severe depression: recurrence and chronicity]. / Dépressions sévères : récurrence et chronicité.

This review paper deals with the question of the relationships between clinical severity of depression, recurrence risk and chronicity risk. About 60% of the subjects with a first episode of major depression will present a second episode lifetime. The risk of recurrence increases slightly with the severity of the index episode. Conversely, depression severity tends to be slightly higher in recurrent episodes as compared with first episodes. This is supported by a few studies of consecutive episodes within the same patients but it could also result from a selection effect. The risk that a depressive episode is still meeting the criteria of a major depressive episode two years after onset is between 10 and 20%. Neither the severity of the index episode nor its recurrent character clearly increases the risk of its chronic evolution. Finally, minor depression (as a dysthymic disorder or residual symptoms) increases the risk of a new major depressive episode. We may conclude that there are only moderate interactions between the clinical severity of depression and the risks of chronicity and recurrence. Worsening of one of these three variables will not result into a dramatic worsening of the two others. In fact, chronicity and recurrence do not specifically contribute to the severity of the next episode, they only contribute to the long-term severity of depressive disorders, which is already by itself a major issue.

[Current topics in pharmacokinetics and pharmacogenetics of antidepressant drugs]. / Actualités pharmacocinétiques et pharmacogénétiques des antidépresseurs.

For antidepressants as well as for other drugs, personalized prescription has become a major challenge, provided the large interindividual variability encountered both at the pharmacokinetic and the efficacy and tolerance levels. Better identification of the numerous relevant factors and quantification of their effects are prerequisites to progress in that direction. On the basis of recent literature, genetic factors are first reviewed, including polymorphisms of genes coding for drug-metabolizing enzymes, transporters and pharmacodynamic target molecules. Current recommendations with respect to therapeutic drug monitoring of antidepressants and use of pharmacogenetic testing are then summarized.

Frequency of dysphoria and mixed states.

BACKGROUND: Mixed states are a complex entity in the field of mood disorders. Dysphoria has been advocated as an important clinical dimension of mixed states. The objective of this work is to study the frequency of dysphoria within a population of patients with DSM-IV major depressive and/or manic episodes and to determine if it may help establish diagnostic criteria for subthreshold cases of depressive or manic mixed states. SAMPLING AND METHODS: A total of 165 patients were assessed using the Mini International Neuropsychiatric Interview complemented by a section defining dysphoria as a constellation of 3 among 4 symptoms (inner tension, irritability, aggressive behavior and hostility). RESULTS: When classifying patients according to the number of symptoms of the opposite polarity, changes in the frequency of dysphoria revealed a clear contrast between the 2 opposite manic and depressive poles and the full mixed state (DSM-IV definition). The frequency of dysphoria was 17.5% in pure depression, 22.7% in pure mania and 73.3% in full mixed state. Two threshold effects were identified: (1) the frequency of dysphoria increased from 17.5 to 61.1% (p = 0.002) when the number of manic symptoms in DSM-IV depressed patients increased from 0 to 1, and (2) dysphoria increased from 14.3 to 69.2% (p = 0.057) when the number of depressive symptoms increased from 2 to 3 in DSM-IV manic patients. CONCLUSION: Dysphoria is strongly but not necessarily associated with mixed states. When used as a clinical marker for mixed states, dysphoria confirms the modern delimitations of sub-threshold mixed states by specifying the required number of symptoms of the opposite polarity (which could be lower for depressive mixed states than for manic mixed states). The study has limitations related to the inclusion of patients who are not drug-free, to the definition of dysphoria and to the sample size.

[The major depression with psychotic symptoms]. / La dépression majeure avec symptômes psychotiques.

The major depression with psychotic symptoms (CIM-10) or psychotic features (DSM-IV) is relatively frequent and probably underdiagnosed. During the last years there is a renewal of interest to better understand its psychopathology and to propose specific psychotherapeutic treatments. Concerning the pharmacological treatment, the discussion is still open about the necessity of the association of an antipsychotic or the choice of the antidepressant.

[Psychiatry]. / Psychiatrie.

Introduced this year on the Swiss market, duloxetine (Cymbalta) is a new antidepressant which inhibits the reuptake of noradrenaline and serotonin. Clinical studies have shown its efficacy in depression as well as in neuropathic pains (60-120 mg/day) with a good tolerability. In this paper are also included short reviews about the two large American studies developed by the National Institute of Mental Health in the fields of the treatment for depression (STAR-D) and of the antipsychotic treatments for schizophrenia (CATIE study). Its also reviews two questions of present interest: the use of the second generation antipsychotics for the treatment of bipolar depression and the concept of bipolar disorders in children.

Incidence and risk factors of venous thromboembolism: Peculiarities in psychiatric institutions.

INTRODUCTION: The objectives of this study were to assess the incidence and risk factors for venous thromboembolism (VTE) in a population of patients hospitalized in a psychiatric setting. MATERIAL AND METHODS: Episodes of VTE occurring in patients hospitalized at the Erstein Hospital (France), specialized in psychiatry, were retrospectively identified from a computerized database. The clinical, somatic, psychiatric and therapeutic characteristics of each patient were analyzed in comparison with a control population composed of patients of similar age and sex, hospitalized during the same period in a psychiatric setting but who did not suffer from VTE. RESULTS: Between January 2012 and October 2015, 12,320 patients were hospitalized. Forty-one patients experienced an episode of VTE, giving an incidence of 47.8per1000patient-years (3.32 cases per 1000 patients). Restriction of mobility (restraint or confinement), somatic clinical profile, psychiatric diagnosis or psychotropic treatment were not associated with an increased risk of VTE. The event occurred within the first 48h of hospitalization for 31.7% of patients, and within the first week for 56.1%. Time to onset for the occurrence of VTE between admission and the end of the first week was significantly associated with acute decompensation of a chronic psychiatric pathology (p=0.003). CONCLUSION: The incidence of VTE in a psychiatric setting is high. Acute decompensation of a chronic psychiatric pathology is associated with a risk of VTE.

A stepwise drug treatment algorithm to obtain complete remission in depression: a Geneva study.

QUESTIONS UNDER STUDY/PRINCIPLES: We describe the proportion of severely depressed outpatients reaching complete remission at the different stages of a drug treatment algorithm. We compare several treatment options for SSRI (selective serotonin reuptake inhibitor) non-responders and test the feasibility of the algorithm in clinical conditions. METHODS: Patients with severe depressive disorders (ICD-10; MADRS > or = 25) admitted to an academic outpatient clinic were enrolled in this algorithm-guided sequential treatment protocol (starting with an SSRI and ending with a tricyclic, lithium, triodothyronine combination). The general principle of the algorithm was to boost the drug therapy in the event of non-response. RESULTS: 135 patients entered the study and 131 were eligible for analysis. From this group, 86 patients dropped out (65.6%), 40 reached complete remission (30.5%) and 5 patients did not reach remission at all (3.8%). In the 117 patients to whom a last observation carried forward approach was applied, the median improvement of the MADRS score was 48.0% (range -20.7%-100%), with 48.7% of patients considered responders, 23.1% partial responders and 28.2% non-responders. Median retention time was 8 weeks (range 2-34). CONCLUSIONS: This algorithm-guided antidepressant treatment was acceptable for clinicians and resulted in an elevated final response rate among study completers. However, the dropout rate was high, mainly due to treatment interruption or non-observance.

[Psychiatry]. / Psychiatrie.

During the year 2005 much of the attention was given to the debate on the risk of suicide during treatments with selective serotonin reuptake inhibitors. Our review concludes with a moderate increased risk of suicidal behaviour but not a risk of death by suicide. Caution, not panic, is indicated, particularly for children and adolescents given that, in this age group, benefits of these drugs have not been well established. We also report two synthesis concerning the latest developments in the fields of cognitive psychotherapy for depressive disorders (rather stimulating news) and of pharmacotherapy for borderline personality disorders (no breaking news).

[Psychiatry]. / Psychiatrie.

The main innovation of the year 2004 was the introduction of a new, second-generation antipsychotic drug with a new mechanism of action (partial dopamine agonist), encouraging first clinical results, and an advantageous clinical tolerance profile. Additionally, three new galenic forms are presented: an oral, extended-release form of methylphenidate that could be useful in the treatment of attention-deficit/hyperactivity disorders; an intramuscular depot form of a second-generation antipsychotic drug (risperidone) with the advantage of improving adherence; and an intramuscular form of a second generation antipsychotic (olanzapine) that is valuable in emergency situations. Finally, we will briefly give an update on the advantages of lamotrigine in bipolar depression.

Can home-monitoring of sleep predict depressive episodes in bipolar patients?

The aim of this study is the evaluation of the autonomic regulations during depressive stages in bipolar patients in order to test new quantitative and objective measures to detect such events. A sensorized T-shirt was used to record ECG signal and body movements during the night, from which HRV data and sleep macrostructure were estimated and analyzed. 9 out of 20 features extracted resulted to be significant (p<;0.05) in discriminating among depressive and non-depressive states. Such features are representation of HRV dynamics in both linear and non-linear domain and parameters linked to sleep modulations.

Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases.

BACKGROUND: Risperidone and olanzapine are atypical antipsychotics that are now widely used in clinical practice. METHOD: A MEDLINE search (1966-1999) showed that, following the introduction of these agents in recent years, 26 cases of induced hypomanic and manic syndromes have been reported during standard olanzapine (N = 10) or risperidone (N = 16) treatment. RESULTS: A critical analysis of these case reports reveals that the effects on mood were sometimes insufficiently documented and that in about half of them (N = 16) evidence is highly suggestive of a causative role of risperidone or olanzapine in the induction of (hypo)manic symptomatology. CONCLUSION: Despite limitations, the available literature confirms intriguing effects of these 2 antipsychotics on mood. The risk factors as well as the mechanisms of action underlying these effects remain to be clarified.

Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation.

The effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram and its metabolites in dextromethorphan/mephenytoin phenotyped patients pretreated with citalopram (CIT) was studied: seven female patients (45.1 +/- 13.9 years) suffering from a major depressive episode [ICD-10: F32.2 (n = 3 patients), F33.2 (n = 2), F32.10 (n = 1) or F32.11 (n = 1)], who were non-responders to a 3-week treatment with 40 mg/day CIT (From day-21 to day 0) (day 0: MADRS score > or = 12), were co-medicated for another 3 weeks with fluvoxamine (50 mg/day from day 1-7, 100 mg/day from day 14-21). All patients were extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6), except one patient, who had a genetic deficiency of CYP2D6. There was a significant increase of the plasma concentrations of S- and R-citalopram from day 0 (27 +/- 14 micrograms/l and 55 +/- 23 micrograms/l, respectively) to day 21 (83 +/- 38 micrograms/l and 98 +/- 44 micrograms/l, respectively), after addition of fluvoxamine (P < 0.02, for each comparison), and the mean ratio S/R-citalopram increased from 0.48 to 0.84. S-Citalopram inhibits more potently 5-HT uptake than R-citalopram: therefore, fluvoxamine increases the pharmacologically more active S-citalopram with some stereoselectivity. According to a previous in vitro study, this pharmacokinetic interaction occurs on the level of CYP2C19, but also of CYP2D6 and CYP3A4 which, in contrast to CYP1A2, contribute to the N-demethylation of citalopram and which are stereoselectively inhibited by fluvoxamine. All but one patient showed clinical improvement by a decrease of the MADRS score by at least 50% and a final score < or = 13 (mean +/- SD: day 0:30.6 +/- 9.2; day 21:11.0 +/- 6.5). Some patients showed minor symptoms, such as nausea and tremor, but the combined treatment was generally well tolerated.

Risperidone and reversible neutropenia: a negative rechallenge.

After 6 weeks of a risperidone rechallenge therapy (2-4 mg/day), no hematological abnormalities were observed in a 26-year-old schizophrenic woman. Two years previously after 9 days of risperidone therapy (2-6 mg/day), the same patient had developed a reversible neutropenia during a cold.

Ultra-rapid opiate detoxification using deep sedation with oral midazolam: short and long-term results.

The present study describes an ultra-rapid opiate detoxification method using direct transition from heroin or methadone to oral naltrexone after deep sedation with oral midazolam in conjunction with ondansetron and clonidine treatment. Twenty patients were detoxified with the method. No serious events occurred, but two out of three patients vomited during the acute phase of deep sedation, which involves some risks. Withdrawal symptoms were still present 24 h after detoxification and 80% of the patients relapsed during a 6-month follow-up.