[Anxiety disorders : from diagnosis to management]. / Les troubles anxieux : du diagnostic au traitement.

Anxiety disorders are very common in the general population. They are associated with a considerable personal suffering and an important economic burden. Comorbidity with mental disorder and physical illness is frequent. The treatment includes pharmacological and psychotherapeutical interventions that have been well validated in scientific studies. Unfortunately, many patients remain undiagnosed and undertreated. Moreover, the efficacy and tolerability of the available pharmacological and psychological treatments are disappointing. That is the reason why prevention has to be a real priority for the medical community and for our authorities.

Les troubles anxieux sont très fréquents dans la population générale. Ils sont associés à une souffrance personnelle considérable et un impact économique important. La comorbidité avec un autre trouble mental et/ou une affection physique est fréquente. Le traitement comprend des interventions pharmacologiques et psychothérapeutiques bien validées sur le plan scientifique. Malheureusement, beaucoup de patients sont toujours sous-diagnostiqués et sous-traités. En outre, l'efficacité et la tolérance des traitements médicamenteux et psychologiques sont souvent décevantes. C'est la raison pour laquelle la prévention doit devenir une véritable priorité pour le monde médical, comme pour nos autorités.

What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram.

OBJECTIVES: Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. METHODS: A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). RESULTS: Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. CONCLUSIONS: Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.

Extended-release quetiapine fumarate (quetiapine XR) monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder.

BACKGROUND: Patients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge. METHODS: This 6-week, randomised, open-label, rater-blinded trial evaluated once-daily extended-release quetiapine fumarate (quetiapine XR; 300 mg/day) as add-on to ongoing antidepressant and quetiapine XR monotherapy (300 mg/day) compared with add-on lithium (0.6-1.2 mmol/L) in patients with treatment-resistant MDD. Primary efficacy measure: change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomisation to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS. RESULTS: At week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229); least squares means (LSM) differences (97.5% CI) in MADRS total score changes were -2.32 (-4.6, -0.05) and -0.97 (-3.24, 1.31), respectively. LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; p<0.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (≥ 50% reduction in total score), MADRS remission (total score ≤ 10, add-on quetiapine XR only) and Clinical Global Impressions ('much'/'very much' improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments. LIMITATIONS: Limitations included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase. CONCLUSIONS: Add-on quetiapine XR (300 mg/day) and quetiapine XR monotherapy (300 mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD.

The hidden third: improving outcome in treatment-resistant depression.

Treatment-resistant depression (TRD) presents many challenges for both patients and physicians. This review aims to evaluate the current status of the field of TRD and reflects the main findings of a consensus meeting held in September 2009. Literature searches were also conducted using PubMed and EMBASE. Abstracts of the retrieved articles were reviewed independently by the authors for inclusion. Evaluation of the clinical evidence in TRD is complicated by the absence of a validated definition, and there is a need to move away from traditional definitions of remission based on severity of symptoms to one that includes normalisation of functioning. One potential way of improving treatment of TRD is through the use of predictive biomarkers and clinical variables. The advent of new treatments may also help by focusing on neurotransmitters other than serotonin. Strategies such as the switching of antidepressants, use of combination therapy with lithium, atypical antipsychotics and other pharmacological agents can improve outcomes, and techniques such as deep brain stimulation and vagus nerve stimulation have shown promising early results. Despite consistent advances in the pharmacotherapy of mood disorders in the last decade, high rates of TRD are still a challenging aspect of overall management.

Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis.

Depressive symptoms and episodes dominate the course of bipolar disorder. However, the therapeutic armamentarium for bipolar depression is limited. Recent evidence points to the efficacy of second generation antipsychotics (SGAs) for the treatment of bipolar depression. We conducted a systematic review and meta-analysis of the efficacy and safety of SGAs (randomized, double-blind, placebo-controlled trials; used in monotherapy) in the treatment of adult patients with bipolar depression. Publication bias was corrected for by performing similar searches using the clinical trials register of the respective pharmaceutical companies, the Cochrane Database and ClinicalTrials.gov. Seven published papers were identified on the use of aripiprazole, olanzapine and quetiapine. Internal validity of the trials was fairly good, external validity only moderate. Different outcome measures of efficacy and safety were assessed. When the individual trials were looked at, quetiapine and to a lesser extent olanzapine demonstrated significant improvement in MADRS (Montgomery-Åsberg Depression Rating Scale) total scores. This was not demonstrated for aripiprazole. Efficacy was hampered by adverse events, such as weight gain, akathisia and somnolence/sedation. Both clinical heterogeneity of the included trials and statistical heterogeneity of the meta-analytic data were considerable. The number of quetiapine trials was disproportionate to the number of trials of aripiprazole and olanzapine. Further research is needed to assess differential efficacy of the different SGAs and their use in clinical practice.

Aripiprazole in patients with bipolar mania and beyond: an update of practical guidance.

BACKGROUND: Aripiprazole is an atypical antipsychotic with a pharmacological and clinical profile distinct from other atypical antipsychotics. SCOPE: A European multidisciplinary advisory panel of university-based experts in bipolar disorders convened in April 2010 to review new clinical guidelines for the management of mania and the role of aripiprazole in its treatment. This report describes the consensus reached on how best to use aripiprazole in the treatment of mania. FINDINGS: Current guidelines recommending aripiprazole for first-line treatment of mania have not generally translated to clinical practice. The panel agreed that clinicians may not feel sufficiently knowledgeable on how to use aripiprazole effectively in mania, and that the perception that aripiprazole is less sedating than other antipschotics may hamper its use. There was consensus about the importance of ensuring that clinicians understood the distinction between antimanic efficacy and sedation. Most acutely manic patients may require night-time sedation, but continuous daytime sedation is not necessarily indicated and may interfere with long-term compliance. If sedation is necessary, guidelines recommend the use of adjunctive benzodiazepines only for a short-time. CONCLUSIONS: Clinical practice guidelines widely recommend aripiprazole as a first-line treatment for mania. Although clinical trials may not represent all patient subpopulations, they show that aripiprazole is well tolerated and has a long-term stabilizing potential. The successful use of aripiprazole rests on using the appropriate initial dose, titrating and adjusting the dose as needed and using appropriate concomitant medication to minimize any short-term adverse events. Low incidence of sedation makes aripiprazole a reasonable long-term treatment choice. If short-term sedation is required an adjunctive sedative agent can be added and removed when no longer needed. Clinical considerations should influence treatment choice, and a better distinction between sedation and antimanic effects should be an educational target aimed to overcome potential barriers for using non-sedative antimanic agents such as aripiprazole.

Duloxetine in major depressed patients resistant to SSRIs and/or venlafaxine.

Several acute depression trials suggest that only 35% of the patients achieve remission state with antidepressant monotherapy. An increasing body of evidence is emerging suggesting that multi-action antidepressants might be more effective in treatment-resistant depressed patients than single-action agents. In this context, the purpose of the study was to assess the effectiveness of duloxetine in treatment-resistant major depressed outpatients. We performed a retrospective study assessing the efficacy of duloxetine in major depressed outpatients who did not achieve full symptom remission (CGI-S (severity) >=3) after treatment of adequate dose and duration (more than 8 weeks) with at least either one SSRI or the SNRI venlafaxine. We excluded patients with a severe medical illness and a personality disorder. CGI-S was used as a measure of symptom severity and administered before the prescription of duloxetine and 6 weeks later. The sample included 29 patients (9 M, 20 F). We observed a very significant decrease in CGI-S scores (4.86 ± 0.51 to 2.17 ± 1.44, p<0.0001) after treatment with duloxetine (dose between 60 and 120 mg). Remission was achieved in 48% of the patients. The tolerance was excellent. This study suggests the potential interest of duloxetine in some treatment-resistant depressed patients.

The TaqI A DRD2 polymorphism in type II alcohol dependence: a marker of age at onset or of a familial disease?

Cloninger's type II is a severe, early-onset, male-limited, and genetically influenced, impulsive form of alcoholism. Significant association has been reported between the A1 allele of the D2 dopamine receptor (DRD2) gene, substance misuse and personality traits of impulsivity and novelty seeking. We assessed the association between the TaqI A DRD2 gene polymorphism with Cloninger's typology and family history of alcohol abuse, which is thought to be more frequent in type II alcoholics. Fifty-one male alcohol-dependent patients were discriminated between type I and type II according to age at onset of alcohol-related problems and interviewed about family history of alcoholism. The associations between DRD2 (A1 or A2 alleles), family history, and typology were assessed by Pearson's chi-square test. Although typology was not associated with the studied polymorphism, a higher rate of general family history of alcohol abuse was still observed in type II patients (chi(2)(1)=4.53; P=.033). Furthermore, the A1 allele of the DRD2 was significantly associated with paternal history of alcoholism (chi(2)(1)=4.66; P=.031) and male, first-degree, collateral history of alcoholism (chi(2)(1)=4.40; P=.036). Age at onset of alcohol-related problems as main discriminator between type I and type II alcohol dependence does not seem to be associated by the TaqI A DRD2 polymorphism. However, the A1 allele of the DRD2 may be a marker of male familial alcoholism, which has been associated with type II alcohol dependence.

The short allele of the serotonin transporter promoter polymorphism influences relapse in alcohol dependence.

AIMS: The short (S) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR) contributes to the risk of alcohol dependence and co-occurring clinical features. We studied the putative link between this allele and relapse. METHODS: 48 alcohol-dependent male patients were recruited and genotyped for the 5-HTTLPR. Relapse to alcohol drinking was monitored during 3 months after standardized withdrawal. RESULTS: The S allele was significantly associated with relapse (p = 0.008) while no other factor that was measured played a significant role. CONCLUSIONS: The S allele of the 5-HTTLPR polymorphism may influence the risk of relapse in abstinent alcohol-dependent patients, possibly through intermediate phenotypes.

Vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior.

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters (n=13) and nonattempters (n=15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29+/-0.13 ng/ml vs 0.36+/-0.21 ng/ml, (F=1.1, df=1, 27, p=0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape.

5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior.

BACKGROUND: Several lines of evidence suggest a clear relationship between serotonin (5-hydroxytryptamine, 5-HT) hypoactivity and suicidal behavior across several psychiatric diagnoses. Few data are available, however, regarding the possible specific role of 5-HT1A receptors in the biology of suicidality. Therefore, the aim of our study was to use a neuroendocrine strategy to test the hypothesis of a role for 5-HT1A receptors in the biology of suicidal behavior. METHODS: Hormonal (adrenocorticotropic hormone [ACTH], cortisol, prolactin [PRL]) and temperature responses after administration of flesinoxan, a highly potent and selective 5-HT1A receptor full agonist, were assessed in 40 inpatients with major depression, divided into two subgroups (20 suicide attempters and 20 nonattempters), compared with 20 normal control subjects matched for gender and age. RESULTS: Compared with nonattempters, suicide attempters exhibited significantly lower PRL (p = .01), cortisol (p = .014), and temperature (p = .0002) responses. Prolactin (p = .007), cortisol (p = .04), and temperature (p = .00003) responses were also decreased in suicide attempters compared with normal control subjects. In contrast, we did not observe any significant differences in hormonal or temperature responses to flesinoxan between depressed patients without a history of suicide attempt and normal control subjects. CONCLUSIONS: The present study tends to confirm the role of 5-HT and more specifically 5-HT1A receptors in the biology of suicidal behavior in major depression.

Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study.

RATIONALE: Flesinoxan is a highly potent and selective 5-HT1A agonist. In a recent study, in normal volunteers, flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. OBJECTIVES: In order to better define the role of 5-HT receptor subtypes in response to flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal and temperature responses to flesinoxan. METHODS: Hormonal and temperature responses were studied in 6 volunteers with or without pretreatment with pindolol (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2 antagonist, using a double-blind crossover design. RESULTS: Pindolol significantly antagonized ACTH, PRL, GH and temperature responses to flesinoxan and ritanserin exhibited similar activity on PRL and ACTH responses. CONCLUSIONS: These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and temperature responses to flesinoxan, and the role of 5-HT2 mechanisms in PRL and ACTH responses. Therefore, they confirm the interest of flesinoxan as a 5-HT neuroendocrine probe.

Event-related potentials to emotional and neutral stimuli in alcoholism.

Several studies have demonstrated that the emotional value of stimuli affects P300 amplitude. In the present study, the influence of alcohol-related stimuli in alcoholic patients was investigated. Subjects were 10 alcoholic inpatients (3 female) and 10 age- and sex-matched controls. Eight alcohol-related and 8 neutral words served as stimuli in a visual oddball paradigm. Acohol-related words were targets (48 stimuli, 33%) and neutral words were standard stimuli (96 stimuli, 66%). Results showed that P300 amplitude for targets did not differ significantly between the two groups. However, P300 latency for targets as well as reaction time were significantly shorter in male alcoholic patients. In contrast, P300 latency was increased in female alcoholic patients but reaction time did not differ. These results suggest that male alcoholics process information linked to alcohol cues more rapidly than neutral cues, probably because a specific semantic network is activated in these patients. The decreased reaction time confirms the impulsive behavior frequently found in male alcoholism, as it has been described in type II alcoholism. Besides, the results imply that information processing was delayed in female alcoholic patients. Therefore this study demonstrates a gender-dependent impact of alcohol-related stimuli on information processing.

Catecholamine and HPA axis dysfunction in depression: relationship with suicidal behavior.

A large body of evidence suggests a potential role for catecholaminergic function as a possible biological factor in the control of suicidal behavior. Recently, we have used a neuroendocrine strategy to study dopaminergic and noradrenergic activities in depressed suicide attempters. However, some problems are associated with the use of growth hormone (GH) response to catecholaminergic challenge, because GH release could be decreased by a direct effect of corticosteroids at the pituitary level. Therefore, the purpose of the present study was to assess GH response to both apomorphine, a dopaminergic agonist, and clonidine, an alpha2-adrenergic agonist, according to the dexamethasone suppression test (DST) status in a sample of 20 major depressed inpatients with a history of suicide attempt compared with nonattempters. Our results tended to show that hypercortisolemia as assessed by post-DST cortisol values did not inhibit GH response to apomorphine or clonidine, suggesting that hypothalamo-pituitary-adrenal axis overactivity does not explain the impaired GH response to apomorphine in major depressed patients with a history of suicide attempt.

Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers.

RATIONALE: Flesinoxan is a highly potent and selective 5-HT(1A) agonist and appears to be a potentially interesting neuroendocrine serotonergic probe. OBJECTIVES: We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to flesinoxan in normal volunteers. METHODS: In a double-blind placebo-controlled study, single doses of 0.5 mg and 1 mg were injected over 10 min into 12 healthy male volunteers at 1-week intervals. Temperature and hormonal responses were measured at times -30, 0, 15, 30, 60, 90, and 120 min. RESULTS: Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Tolerance to flesinoxan was excellent. CONCLUSIONS: These results showed the role of 5-HT(1A) mechanisms in the PRL, ACTH, cortisol, GH, and temperature responses to flesinoxan. In the present study, flesinoxan appears a very promising serotonergic neuroendocrine probe.