Nicola Gervasoni

Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode.

We had previously reported decreased serum brain-derived neurotrophic factor (BDNF) levels in depressed patients. In the present study, we tested the hypothesis that antidepressant treatment would normalize serum BDNF levels, at least in a subgroup of patients. Major depressed patients (15 females and 11 males) diagnosed according to DSM-IV criteria and healthy controls (13 females and 13 males) participated in this study. Serum BDNF was assayed with the ELISA method for depressed and remitted patients and the severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale. An analysis of variance showed that treatment had an effect [F(1, 24) = 4.46, p = 0.045] on the normalization of serum BDNF levels. We also found a correlation between the severity of depression (r = 0.51, p = 0.008), the pretreatment BDNF levels (r = 0.62, p = 0.001) and the difference in serum BDNF levels after antidepressant treatment. These results suggest that antidepressant treatment has a positive effect on serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders.

CYP2D6 and ABCB1 Genetic Variability : Influence on Paroxetine Plasma Level and Therapeutic Response

Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns. The present study investigates plasma concentration and therapeutic response to paroxetine for the influence of age, sex, and CYP2D6 and ABCB1 polymorphisms, the latter gene encoding for the permeability glycoprotein. Genotyping for CYP2D6 (alleles *3, *4, *5, *6, and *xN) and ABCB1 polymorphisms (61A>G, 2677G>T, and 3435C>T) was performed in 71 depressed patients who started 20 mg paroxetine per day and had plasma concentration measured after 2 weeks at a fixed dose. A dose increase to 30 mg per day was possible starting at week 2. For 63 patients, severity of depression (Montgomery-Åsberg Depression Rating Scale) was assessed at weeks 0, 2, and 4 and every 2 weeks thereafter until discontinuation. Persistent response was defined as 50% improvement from baseline score sustained from the first occurrence to study end point. Paroxetine concentration significantly differed between female and male patients (median, 28 versus 16 ng/mL; P = 0.001). Differences were not significant between CYP2D6 heterozygous and homozygous extensive metabolizers (median, 27 versus 22 ng/mL; P = 0.074) and between ABCB1 genotypes (P > 0.10). When considered in a multivariate model, CYP2D6 heterozygous extensive metabolizer phenotype (P = 0.062) and female gender (P = 0.001) predicted 1.3-fold and 1.6-fold higher paroxetine concentration, respectively, but fraction of explained variability was modest (21%). Frequency of persistent response at study end point did not significantly differ according to CYP2D6 heterozygous extensive metabolizer versus homozygous extensive metabolizer phenotype and ABCB1 polymorphisms in univariate analyses. After adjusting for age, sex, paroxetine concentration at week 2, and daily dose at study end point, ABCB1 genotype contributed to improving the model significantly for 61A>G (P = 0.043), but not 2677G>T (P = 0.068) and 3435C>T (P = 0.11). None of two poor metabolizers and four ultrarapid metabolizers showed persistent response to paroxetine. The hypothesis that permeability glycoprotein activity might be a relevant predictor of therapeutic response deserves to be further investigated while controlling for pharmacokinetic variability.

The cortisol awakening response in patients remitted from depression

An impressive number of data has been accumulated on dysfunctions of the hypothalamo-pituitary-adrenal (HPA) axis and cortisol hypersecretion in depression. To assess the dynamic HPA functioning, the cortisol awakening response (CAR) is an easily accessible and reliable approach. Some data suggest that elevated CAR in depressed patients has trait-like characteristics. Therefore we investigated whether patients in remission from a depressive episode have elevated CAR compared to control subjects. CAR of thirty-eight patients in remission from depression (11 men, 27 women, age range 24-66) and 52 control participants were analyzed (18 men, 34 women, age range 24-63). All patients had experienced ≥3 previous depressive episodes and were off psychotropic medication since at least 3 months. Saliva samples were collected only once, at home, either on weekend or weekday at 0, 15, 30, 45 and 60 min post-awakening. The area under the curve (AUC) above minimum cortisol concentration displayed large interindividual variability (6.4-fold in remitted patients and 8.1-fold in controls, based on 80% range). Investigation of possible variability factors showed that percent explained variance increased from 3.9% when group was considered alone to 8.8%, 12.3% and 19.2% after adjusting for significant effects of weekday vs. weekend, wake-up time and sleep duration, respectively. According to the latter model, AUC was estimated to be 51% higher in remitted patients than in controls (p = 0.007), while a 21% AUC decrease was associated with a 1-h longer sleep duration (p<0.001). In future studies, detection of between-group differences might benefit from adjusting for sleep duration and other possible confounders.

Performance of the Mood Disorder Questionnaire (MDQ) according to bipolar subtype and symptom severity

OBJECTIVE To evaluate the performance of the French version of the Mood Disorder Questionnaire (MDQ) in patients attending a general psychiatric outpatient service as well as whether MDQ scores are independent of patient mood state at time of completion. METHOD 183 patients completed the MDQ and were assessed with the MADRS and YMRS scales, before being interviewed with the SCID (time 1). MDQ, MADRS and YMRS assessment was repeated four to six weeks later (time 2). RESULTS According to the SCID, 44 patients were suffering from bipolar spectrum disorder and 102 from unipolar disorder (37 patients dropped out). The MDQ provided high specificity (83.3%). Sensitivity was 63.6%, with better identification of bipolar I (85.0%) than bipolar II patients (45.8%). In the whole sample, test-retest reliability was satisfactory (kappa=0.64). Modest correlations were observed between the number of endorsed MDQ items and YMRS scores at time 1 (Spearman r=0.19; p=0.021) and time 2 (r=0.26; p=0.002). CONCLUSIONS Despite some fluctuations over time and a discrete influence of symptom severity, the screening algorithm can be used reliably, whether in the acute or remission phase of a depressive episode.

Pharmacogenetic study on risperidone long-acting injection: influence of cytochrome P450 2D6 and pregnane X receptor on risperidone exposure and drug-induced side-effects.

AbstractRisperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.

Self-rated residual symptoms do not predict 1-year recurrence of depression ☆

BACKGROUND Residual depressive symptoms are generally documented as a risk factor for recurrence. In the absence of a specific instrument for the assessment of residual symptoms, a new 25-item Depression Residual Symptom Scale (DRSS) was elaborated and tested for recurrence prediction over a 1-year follow-up. SAMPLING AND METHODS Fifty-nine patients in remission after a major depressive episode (MDE) were recruited in two centres. They were assessed with the DRSS and the Montgomery-Asberg Depression Rating Scale (MADRS) at inclusion and followed for 1 year according to a seminaturalistic design. The DRSS included specific depressive symptoms and subjective symptoms of vulnerability, lack of return to usual self and premorbid level of functioning. RESULTS Severity of residual symptoms was not significantly associated with increased risk of recurrence. However, DRSS score was significantly higher among patients with three or more episodes than one to two episodes. Number of previous episodes and treatment interruption were not identified as significant predictors of recurrence. CONCLUSION The proposed instrument is not predictive of depressive recurrence, but is sensitive to increased perception of vulnerability associated with consecutive episodes. Limitations include small sample size, seminaturalistic design (no standardisation of treatment) and content of the instrument.

Is there a place for tricyclic antidepressants and subsequent augmentation strategies in obtaining remission for patients with treatment resistant depression

Major depressive disorder is a worrying mental health problem and obtaining remission from treatment resistant depression (TRD) remains an important clinical issue. Twenty patients (14 women, 6 men) considered as treatment resistant after the fourth step of a seven-step treatment algorithm to obtain remission in major depression received clomipramine 150 mg/day for 1 month (step 5). In case of failure, two subsequent augmentation strategies with lithium and lithium plus triiodothyronine (T3) were implemented. Median Montgomery-Asberg Depression Rating Scale (MADRS) score at initiation of clomipramine treatment was 29 (range 8-43). Treatment with clomipramine alone allowed five patients to achieve sustained remission (MADRS < or = 8), while three patients were responders (MADRS decrease > or = 50%) and three patients were partial responders (MADRS decrease > 25%). Lithium augmentation in 10 patients led to one additional remission, whereas no additional remission was observed in 6 patients with further T3 augmentation. Tricyclic antidepressants have demonstrated efficacy in TRD. The present study suggests that treatment with clomipramine might allow obtaining remission in some patients who do not fully respond despite multiple interventions.

Subjective Experience of Thought Overactivation in Mood Disorders: Beyond Racing and Crowded Thoughts

Background: Racing thoughts, crowded thoughts and flight of ideas are frequent symptoms in mood disorders, but the underlying subjective experience of overactivation of thought processes remains poorly documented. Methods: Qualitative analysis of audiotaped interviews explored subjective experience of thought overactivation in patients with mood disorders (sample 1, n = 45). Quantitative analysis considered the properties of a newly developed rating scale in sample 1, in an additional sample of patients with mood disorders (sample 2, n = 37) and in healthy subjects (sample 3, n = 38). Results: Qualitative analysis of individual interviews revealed that 5 conceptual categories characterized thought overactivation: sequential thought flow, overstimulation, competition for resource allocation, unexpected/unexplained onset, and association with mood and emotions. A principal component analysis of the initial 16-item rating scale indicated that a single component explained 55.9% of the variance, with major and exclusive contributions from 9 items, which were retained in the final 9-item Subjective Thought Overactivation Questionnaire (STOQ; Cronbachs α = 0.95). Total score correlated significantly with activation, depression and perceived conflict subscales of the Internal State Scale (ISS; rs = 0.57-0.66, p < 0.001). It was associated with decreased well-being (ISS; rs = -0.48, p = 0.001) and increased state anxiety (State-Trait Anxiety Inventory; rs = 0.60, p < 0.001). The STOQ score was significantly higher in patients than in healthy subjects. It allowed distinguishing between ISS mood states, with the highest median score in mixed states. Limitations: Sample size, representativeness, possible bias in qualitative analysis, and quality of expert consensus. Conclusions: Qualitative analysis of clinical interviews, together with a new short rating scale, contributed to a documentation of subjective thought overactivation, an important but often undetected feature in mood disorders.

Early telephone intervention for psychiatric outpatients starting antidepressant treatment.

Background: The article addresses the hypothesis that early telephone intervention for psychiatric outpatients starting antidepressant treatment would increase compliance with pharmacological treatment and retention time in the study, and thus allow for a more favourable clinical outcome. Methods: The study focuses on 131 depressed outpatients who participated in a study aiming to obtain full remission. Patients who benefited from three early structured telephone interventions (n=81) were compared with participants who benefited from the usual care (n=50) with no clinical contact before the first clinical assessment at 2 weeks. Results: The intervention proved to have no significant effect on treatment adherence, attrition rate, exclusion rate for adverse events or improvement of depression severity. It was nevertheless associated with increased retention time in the present study. Conclusions: These results suggest that motivational phone calls may reinforce adhesion in psychiatric patients and provide early opportunities to adapt treatment to individual needs. Clinical implication: These results suggest that motivational phone calls may reinforce adhesion in psychiatric patients and provide early opportunities to adapt treatment to individual needs.

P.2.a.010 The cortisol awakening response in patients remitted from depression

J.M. Aubry1 °, F. Jermann1, M. Gex-Fabry1, L. Bockhorn2, M. Van der Linden3, N. Gervasoni4, G. Bertschy1, F.M. Rossier2, G. Bondolfi1. 1University Hospitals, Department of Psychiatry, Geneva, Switzerland; 2University Hospitals, Department of Genetics and Laboratory Medicine Service of Endocrinology and Diabetology, Geneva, Switzerland; 3University of Geneva, Cognitive Psychoplogy and Neuropsychology Unit, Geneva, Switzerland; 4University of Geneva and Clinique la Metairie, Academic Department of Psychiatry, Geneva and Nyon, Switzerland