Florian Ferreri

Current research on cognitive aspects of anxiety disorders

Purpose of review Cognitive dysfunction is frequently reported in anxiety disorders. Our aim is to describe recent advances concerning these cognitive aspects. Recent findings Cognitive dysfunction in anxiety disorders can be classified into four domains. The first concerns executive functions, mainly attentional processes. The second concerns memory, including deficits in working, episodic, and autobiographical memory. The third encompasses maladaptive cognitions, or thoughts and beliefs. Finally, a burgeoning area of research (mainly in obsessive–compulsive disorder and posttraumatic stress disorder) concerns metacognitions, or thoughts and beliefs about ones own thoughts and beliefs. All of these dysfunctions may contribute to maintain or aggravate anxiety disorders. When developing and implementing interventions, researchers and clinicians alike must consider these cognitive aspects, and may need to tailor their approaches accordingly. Summary Advances have clearly been made in the elucidation of the cognitive functioning associated with anxiety disorders. It remains unclear if particular cognitive profiles can help to distinguish anxiety disorders from one another, although emerging evidence suggests this may be the case. Further clarification will add to our understanding of the development and maintenance of these disorders, and may provide targets for future therapy and endophenotypes.

Recognition and management of neuropsychiatric complications in Parkinson's disease

Parkinsons disease is primarily considered a motor disease characterized by rest tremor, rigidity, bradykinesia and postural disturbances. However, neuropsychiatric complications, including mood and anxiety disorders, fatigue, apathy, psychosis, cognitive impairment, dementia, sleep disorders and addictions, frequently complicate the course of the illness. The pathophysiologic features of these complications are multifaceted and include neuropathophysiologic changes of a degenerative disease, exposure to antiparkinsonian treatments and emotional reactions to having a disabling chronic illness. Changes in mental status have profound implications for the well-being of patients with Parkinsons disease and of their caregivers. Treatment is often efficacious but becomes a challenge in advanced stages of Parkinsons disease. In this article, we review the key clinical features of neuropsychiatric complications in Parkinsons disease as well as what is known about their epidemiologic characteristics, risk factors, pathophysiologic features and management.

PTSD in the elderly: the interaction between trauma and aging

BACKGROUND Because an increasingly large cohort of individuals is approaching their elderly years, there is concern about how the healthcare system will cope with the greater demands placed upon it. One area of concern is the impact of trauma and post traumatic stress disorder (PTSD) in the aged. Although several reviews have highlighted the lack of knowledge and research on the topic, there still remain gaps in the literature. Nevertheless, some recent behavioral, endocrinological and neuroimaging studies may provide new insights into the discussion. The central aims of this paper are to summarize the etiological, epidemiological and clinical aspects of PTSD, trauma, and the elderly, and to integrate this knowledge with (i) what is known about PTSD in adults, and (ii) the behavioral, hormonal and cerebral changes associated with healthy aging. METHODS A comprehensive search was performed with ISI Web of Science and PubMed for articles pertinent to the psychology and biology of PTSD, trauma, and the elderly. RESULTS There exist both significant similarities and differences between adults and elderly with PTSD concerning cognitive and biological profile. Evidence suggests that PTSD in the elderly does not follow a simple clinical trajectory. CONCLUSIONS PTSD in the elderly must be considered within the context of normal aging. Strong claims about an interaction between PTSD and aging are difficult to make due to sample heterogeneity, but it is clear that PTSD in this age group presents unique aspects not seen in younger cohorts. Further research must integrate their studies with the biological, psychological, and social changes already associated with the aging process.

Management of post traumatic stress disorder after childbirth: a review

Prevalence and risk factors for the development of post traumatic stress disorder (PTSD) after childbirth is well described in the literature. However, its management and treatment has only begun to be investigated. The aim of this article is to describe the studies that examine the effects of interventions on PTSD after childbirth. MedLine, PILOTS, CINAHL and ISI Web of Science databases were systematically searched for randomised controlled trials, pilot studies and case studies using key words related to PTSD, childbirth, treatment and intervention. The reference lists of the retrieved articles were also used to supplement the search. A total of nine studies were retrieved. Seven studies that examined debriefing or counselling were identified; six randomised controlled trials and one pilot study. Also found were one case report describing the effects of cognitive behavioural therapy (CBT) on two women, and one pilot study of eye movement desensitisation and reprocessing (EMDR). Overall, there is limited evidence concerning the management of women with PTSD after childbirth. The results agree with the findings from the non-childbirth related literature: debriefing and counselling are inconclusively effective while CBT and EMDR may improve PTSD status but require investigation in controlled trials before conclusions could be drawn.

Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohort

Recent data (1–4) show a high comorbidity between major depressive disorder and metabolic syndrome (MetS) (5), a cluster of risk factors for cardiovascular diseases and type 2 diabetes including high waist circumference, high blood pressure, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and high fasting plasma glucose. In a context of increasing prescription of antidepressant medication (6) and evidence of weight gain induced by antidepressants (7), the impact of antidepressant treatment on MetS has to be clarified. Indeed, there has been no prospective study of reasonable sample size and duration addressing the incidence of MetS in patients with major depressive episode treated with antidepressants. This question was addressed in the METADAP, a 6-month prospective, multicentric, real-world treatment observational cohort study of 624 patients with a diagnosis of major depressive disorder and a current major depressive episode. Data were collected from November 2009 to March 2013 in six university psychiatry departments in France. Consecutive in- or out-patients, aged 18 to 65 years, with a current major depressive episode in a context of major depressive disorder (with a minimum score of 18 at the Hamilton Depression Rating Scale-17, HDRS-17) were assessed for MetS at the start of the index antidepressant treatment (M0), and one (M1), three (M3) and six (M6) months later. All of them provided their written informed consent. Patients with psychotic symptoms, bipolar disorders, psychotic disorders, eating disorders, current substance abuse or dependence, pregnancy, organic brain syndromes or severe unstable medical conditions were not included. Patients receiving antipsychotics or mood stabilizers before inclusion and/or for 4 months or more during the last year were also excluded. Antipsychotics, mood stabilizers and stimulants were not permitted during the study, because of their metabolic effects. Benzodiazepines at the minimum effective dose and for the minimum time period and psychotherapies were allowed. The index antidepressant treatment had to be a monotherapy. The drug and its dose were left to the treating psychiatrist, using “real world” treatment options. MetS was diagnosed according to the International Diabetes Federation definition (8). Participants had to have fasted and abstained from strenuous physical activity for 8 hours before examination. Triglycerides, HDL cholesterol and fasting plasma glucose levels were assessed using routine standardized laboratory methods. Thereafter, an assistant investigator blind to the major depression assessment measured waist circumference and blood pressure. Mixed-effects multivariate models were used, because they are a well-accepted method for analyzing longitudinal clinical data in which missing or mistimed observations are present (9). All regression models included main effects for time since initiation of current antidepressant treatment, age, gender, HDRS-17 score at baseline, lifetime duration of prior major depressive disorder, lifetime duration of prior antidepressant medication, antidepressant-free period before inclusion, and current antidepressant classes. Of 689 pre-included patients, 643 were included, of whom 19 had major deviations to the protocol. Thus, 624 patients were analyzed. Six had missing data for MetS at baseline. Patients’ mean age was 45.6±13.2 years; 68.7% were women, 87.5% were inpatients at baseline. Their mean HDRS-17 score at baseline was 24.7±5.0. Their mean number of previous major depressive episodes was 1.9±2.1. The average lifetime duration of major depressive disorder before inclusion was 11.5±12.2 years. The lifetime duration of antidepressant drug treatment before inclusion was 2.3±4.1 years. Upon inclusion, 22.7% of patients were antidepressant naive. The administered antidepressant was a selective serotonin reuptake inhibitor (SSRI) in 38.9% of cases, a serotonin norepinephrine reuptake inhibitor (SNRI) in 38.3%, a tricyclic antidepressant (TCA) in 8.8%, and another one in 14.0%. The mean duration of follow-up was 4.9±4.6 months. The drop-out rate was 25.9% before M1, 21.8% between M1 and M3, and 14.3% later. The main reasons for drop-out were antidepressant change (28.4%), prescription of antipsychotics or mood stabilizers (29.4%), and lost to follow-up (20.4%). In patients without MetS at baseline (N=442, 70.8%), the incidence of MetS was 11.7% at M3 and 16.5% at M6. This increase was significant (mixed-effect multivariate logistic regression: OR=2.29, 95% CI: 1.69-3.10, p<0.0001). It was observed within both the SSRI (0% to 16.2%, p<0.001) and the SNRI group (0% to 16.1%, p=0.001). This increase was independent from other factors, such as age, lifetime duration of prior antidepressant medication, and presence of an antidepressant-free period at baseline. The number of altered components of MetS significantly increased with time (M0: 1.2±0.9, M3: 1.3±1.1, M6: 1.5±1.2; mixed-model multivariate Poisson regression: incident risk ratio, IRR=1.06, 95% CI: 1.02-1.09, p<0.0001). It was significantly higher in patients treated with SNRIs than in those treated with SSRIs (IRR=1.45, 95% CI: 1.16-1.80, p=0.001), and it was lower amongst patients who were antidepressant-free at baseline (IRR=0.81, 95% CI: 0.65-0.99, p=0.03). These effects were independent from each other, from age and gender. In patients with MetS at baseline, mixed-effect multivariate linear regressions showed significant increases over time of supine blood pressure (M0: 123.2±16.4 mmHg, M3: 124.8±13.9 mmHg, M6: 126.8±15.0 mmHg, p<0.05) and fasting plasma glucose (M0: 0.98±0.29 g/l, M3: 1.07±0.48 g/l, M6: 1.03±0.31 g/l, p<0.01), which were independent from other factors. The highlight of this study is the early and significant incidence of MetS after initiation of treatment with antidepressants. The majority of cases occurred in the first three months of treatment. A significant worsening of MetS was also observed in patients who already had the syndrome at baseline. Taken together, these results suggest that treating major depressive episodes with antidepressants can induce or worsen MetS. Specific recommendations for the prevention of MetS in patients with major depressive disorder receiving antidepressant medication are needed. Further studies assessing the underlying mechanisms of this phenomenon are warranted.

Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients

BACKGROUND Whether the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphism can predict antidepressant drug efficacy in depressed patients remains unclear, suggesting that it may depend on antidepressant classes. We assessed the impact of Val66Met polymorphism on antidepressant response and remission depending on antidepressant classes. METHODS In a 6-month prospective, real-world setting, treatment study, 345 Caucasian depressed patients requiring a new or different drug treatment with a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenalin reuptake inhibitor (SNRI) or a tricyclic antidepressant (TCA), were genotyped and assessed for response and remission. RESULTS 231 (67%) patients were homozygous for the Val66 allele (Val/Val) and 114 (33%) were carriers of Met allele (Met). 152 (44.1%) patients were treated with SSRI, the others with SNRI/TCA. Both response and remission were explained by interactions between the Val66Met polymorphism and antidepressant drug classes (multivariate models adjusted for propensity-scores: p=0.02 and p=0.03 respectively). With SSRI, Val/Val patients had a higher response rate 3 months post-treatment than Met patients (68.1% versus 44%; adjusted-OR: 3.04, IC95% [1.05; 9.37], p=0.04). With SNRI/TCA, Val/Val patients had a lower remission rate 6 months post-treatment than Met patients (33.3% versus 60.9%, adjusted-OR: 0.27, IC95% [0.09; 0.76], p=0.02). LIMITATIONS Limited sample size. CONCLUSIONS This study argues for a personalized prescription of antidepressants in Caucasian patients with major depressive disorder, based on the BDNF Val66Met polymorphism: SSRI should be preferred for Val/Val patients and SNRI/TCA for Met patients. Further studies are required to confirm these data.

Inter-relationships between isotretinoin treatment and psychiatric disorders: depression, bipolar disorder, anxiety, psychosis and suicide risks

Isotretinoin (Accutane) is a treatment for severe acne that is resistant to other forms of treatment, including antibiotics and topical treatments. The prescription of this drug has been controversial ever since its initial marketing in 1982. It is the only non-psychotropic drug in the Food and Drug Administration top 10 drugs found to be associated with depression. Recently, Bremner et al published an extensive review (until 2010) of the evidence for the association of retinoic acid (RA) with depression and suicide. Some patients who are admitted in psychiatric hospitals report a history of present or past treatment with isotretinoin. Then, the imputability of the molecule in the occurrence of disorders represents necessarily an important question for both professionals and their patients. This paper aims to specify the links between the drug and specific psychiatric disorders. A review of the literature related to isotretinoin, RA, vitamin A, depression, suicide, anxiety, bipolar disorder, psychosis, schizophrenia was performed. Many studies demonstrated an increased risk of depression, attempted suicide and suicide following isotretinoin treatment. However, isotretinoin may have an antidepressant impact, according to some dermatological papers. They consider treating acne with this efficient treatment could improve self-image and make the patient feel better. Several studies showed that patients with bipolar disorder had an increased risk for a clinical exacerbation of symptoms undergoing treatment with isotretinoin. A few studies also seem to suggest a possible link between isotretinoin and psychosis. Nonetheless, studies point out a link between retinoid dysregulation and schizophrenia through modulation of dopamine receptors. From this review, we propose guidelines for isotretinoin prescription to healthcare professionals.

Abnormal transbilayer distribution of phospholipids in red blood cell membranes in schizophrenia

Abnormalities in membrane lipids have been repeatedly reported in patients with schizophrenia. These abnormalities include decreased phosphatidylethanolamine (PE) and n-3 and n-6 polyunsaturated fatty acids in peripheral and brain cell membranes. The present study investigates the hypothesis of an overrepresentation of PE in the external leaflet of the red blood cell (RBC) membrane in patients with schizophrenia. The assumption was that this modification of PE asymmetrical distribution could explain the reported lipid membrane abnormalities. Phosphatidylethanolamine located in the external leaflet was specifically labeled in RBC membranes from 65 medicated patients with schizophrenia and 38 healthy controls. Labeled (external) and non-labeled (internal) PE and their respective fatty acid composition were analyzed by mass spectrometry. A significant increase in the percentage of external leaflet PE was found in RBC membranes in 63.1% of the patients. In this subgroup, a significant depletion of n-3 and n-6 polyunsaturated fatty acids from internally located PE was also observed. Age, sex and antipsychotic treatment were not associated with the transbilayer membrane distribution of PE. Potential mechanisms underlying these abnormalities may involve membrane phospholipid transporters or degradative enzymes involved in phospholipid metabolism. The anomaly described could characterize a subgroup among patients with schizophrenia.

Normal and Pathological Aging of Attention in Presymptomatic Huntington’s, Huntington’s and Alzheimer’s Disease, and Nondemented Elderly Subjects

Background: Attention models view attention as having at least two components: endogenous attention defined as executive and directed by voluntary acts, and exogenous attention defined as automatic and directed by external stimulation. Methods: Three studies (2 of our own) were designed to evaluate the decline of these two components of attention in normal aging and two neurodegenerative diseases. Standardized tests derived from Posner’s model of visuospatial attention were administered to normal healthy elderly participants (n = 13), patients suffering from Huntington’s disease (HD; n = 17) and Alzheimer’s disease (n = 15), and matched control subjects (n = 57). Outcome measures were reaction time (RT) and RT difference score (defined as invalid RT minus valid RT). Results: In healthy elderly participants, the decline was more pronounced for endogenous attention in situations of perceptual conflict. In Alzheimer’s disease, there was a significant decline in both attention components, while in HD, voluntary attention was markedly impaired and automatic attention preserved. Conclusions: Normal aging and HD are characterized by decreased endogenous attention in situations of perceptual conflict. Our data support previous findings that older people display impairment of attention in complex perceptual situations. We propose a model which allows for the separation of attention pathologies, thus improving therapeutic strategies for patients and elderly.

Severe insomnia is associated with hypertriglyceridemia in women with major depression treated in psychiatry settings

BACKGROUND Hypertriglyceridemia (HTG) is a cardiovascular risk factor. In the general population, elevated fasting triglyceridemia (TG) is associated with insomnia. Since insomnia is a core symptom of Major Depressive Episodes (MDE), we studied the association of severe insomnia with HTG in major depression. METHODS We used the baseline data of the METADAP cohort, comprising 624 patients with a current MDE in a context of Major Depressive Disorder treated in psychiatry settings, without current alcohol use disorders. Patients were screened for severe insomnia, defined by a score of four or more on the three Hamilton Depression Rating Scale (HDRS) sleep items, and for HTG characterised by TG≥200mg/dL. RESULTS Severe insomnia was observed in 335(54%) patients with a current MDE, of whom 234(70%) were women; 49(8%) patients had HTG, of whom 25(51%) were women. 69(11%) patients were treated with lipid-lowering drugs. Severe insomnia was associated with a higher frequency of HTG in the whole sample (9.9% vs 5.6%, p=0.046) and in the subgroup of women (9.0% vs 2.0%, p=0.002). Multivariate logistic regression analyses adjusted for age, education levels, BMI and total HDRS scores confirmed the association between severe insomnia and HTG in the whole sample (OR=2.02, 95%CI [1.00-4.08], p=0.05) as well as in the subgroup of women (OR=4.82, 95%CI [1.5-15.5], p=0.008). No association was shown in men. PERSPECTIVES HTG should be systematically investigated in depressed patients with severe insomnia and particularly in women. Further studies are needed to explain the association we observed between severe insomnia and HTG.