Jean-Michel Azorin

Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [125I]-DOI

Abnormalities in the serotonergic system have been implicated in the pathophysiology of depressive disorders. Human platelets possess serotonin-2A (5-HT(2A)) receptors, and previous research using LSD or ketanserin as ligands have indicated that their number is increased in depressed patients. Compared to other ligands previously used in platelet studies, DOI is highly selective for the 5-HT(2A) receptor and binds to its high-affinity state, therefore labeling only the receptors that are biologically coupled to the G-protein. We determined the density (Bmax) and the affinity (Kd) of 5-HT(2A) receptors labeled by [(125)I]-DOI in platelets from 21 untreated patients with major depression and 21 healthy volunteers. The density of the 5-HT(2A) binding sites was found to be increased in platelets from female depressed patients as compared to controls. No changes were observed in the Kd. We did not find any relationship between the binding parameters and either the severity of the depressive episode or the suicidal tendencies of the patients. Our results show that the number of coupled platelet 5-HT(2A) receptors is increased in depressed patients, indicating that platelet 5-HT(2A) receptor function is enhanced in depression.

Increased risk of suicide attempt in bipolar patients with severe tobacco dependence

BACKGROUNDnThe aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt.nnnMETHODSnA total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP.nnnRESULTSnThe risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior.nnnCONCLUSIONSnWe found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results.

Red blood cell l-tryptophan uptake in depression. II. Effect of an antidepressant treatment

The evolution of the kinetic parameters, maximal velocity (Vmax) and Michaelis constant (Km), of L-tryptophan (L-TRP) uptake into red blood cells (RBC) was studied in 30 depressed patients in a drug-free state (D0) and after 1 week (D7) and 4 weeks (D28) of a treatment involving a variety of antidepressant drugs, including SSRIs and tricyclics. At D0, 76% of patients exhibited abnormal values of Vmax, which were either higher (36%) or lower (40%) than the control range (control Vmax mean +/- 1 S.D.). High and low Km values were observed in parallel with high and low Vmax values. At D7, individual values of Vmax varied drastically compared to their corresponding value at D0, whatever the pretreatment value of the parameter. The magnitude of the Vmax variation during the first week of treatment was found to be significantly larger in the treatment responders than in the non-responders. At D28, Vmax values of all the responders to treatment were within the control range, whatever their pretreatment Vmax value. On the contrary, non-responders had Vmax values that were significantly lower than those of the controls. Changes in Km followed changes in Vmax during antidepressant treatment. In conclusion, normalization of L-TRP transport kinetics was concomitant with a clear alleviation of depressive symptoms, indicating that RBC L-TRP uptake is dependent on clinical state. Moreover, early reactivity of the Vmax as soon as the first week of treatment may be useful as a predictive index of clinical outcome at D28.

Emotional reactivity, functioning, and C-reactive protein alterations in remitted bipolar patients: Clinical relevance of a dimensional approach

Objectives: Inter-episode mood instability has increasingly been considered in bipolar disorder. This study aimed to investigate emotional reactivity as a major dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms and functional status. This study also aimed to investigate whether high-sensitivity C-reactive protein, a marker of low-grade inflammation, could be a biological marker of emotional dysregulation in bipolar disorder (BD). Methods: Cross-sectional study of 613 subjects who met Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition criteria for BD recruited from the FondaMental Advanced Centers of Expertise in Bipolar Disorders cohort from 2009 to 2014. All patients had been in remission for at least 3u2009months before assessment. Patients were classified into three groups according to levels of emotional reactivity. Emotional reactivity was assessed by using the Multidimensional Assessment of Thymic States, and functional status was assessed by the Functioning Assessment Short Test. Clinical characteristics and blood sample were collected from all patients. Results: In total, 415 (68%) patients had abnormal emotional reactivity. Independent of potential confounders, including age, gender and subthreshold mood symptoms, serum levels of high-sensitivity C-reactive protein were significantly higher in patients with emotional hyper-reactivity (medianu2009=u20094.0u2009mg/L, interquartile rangeu2009=u20092.7–5.6), and with emotional hypo-reactivity (medianu2009=u20093.0u2009mg/L, interquartile rangeu2009=u20091–4) compared with patients with normal emotional reactivity (medianu2009=u20090.95u2009mg/L, interquartile rangeu2009=u20090.4–1.9, pu2009<u20090.001). Patients with emotional hyper-reactivity showed significant cognitive functioning impairment (pu2009<u20090.001). Conclusions: Emotional reactivity appears to be a relevant dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms. Levels of high-sensitivity C-reactive protein may be an objective marker of emotional dysregulation in BD. Further studies are needed to confirm our findings.

Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers

1. Kinetic parameters of red blood cell (RBC) L-triiodothyronine (T3) initial uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 34 untreated inpatients suffering from unipolar depression and in 40 healthy volunteers. 2. Both Vmax and Km were significantly increased in depressed patients as compared to controls. The alterations in kinetic parameters were not associated with the severity of depression. 3. Out of the 19 depressed patients who were submitted to TRH test, 7 of them (36%) showed a blunted TRH-induced TSH response associated with a Vmax situated outside the control mean value +/- 1 S.D. 4. The authors found a significant positive correlation between Vmax of RBC L-T3 and L-tryptophan (TRP) uptakes which is in agreement with the assumption that L-T3 and L-TRP share a common carrier system at the erythrocyte level. 5. The results indicate that the uptake of L-T3 by RBC is increased in major depression. These transport perturbations might reflect alterations in the plasmatic metabolism of L-T3. Evaluation of RBC L-T3 uptake could be useful in a best biological characterization of the depressed patients with regard to their thyroid function.

Decrease in red blood cell l-tryptophan uptake in schizophrenic patients: possible link with loss of impulse control

1. Kinetic parameters of erythrocyte L-tryptophan (TRP) uptake (Vmax, maximal velocity and Km, Michaelis constant) were determined in 19 neuroleptic-free schizophrenic patients and in 19 healthy volunteers. Both Vmax and Km values were significantly lower in schizophrenic patients than in controls. 2. Mean Vmax value was found to be lower in patients who had attempted suicide than in patients who had not. No difference was observed when patients were subdivided on the basis of the violence of suicide attempts. 3. A significant negative correlation was observed between Vmax and scores on the loss of impulse control item as assessed on the PANS scale. 4. Decrease in red blood cell L-TRP uptake reflects a disturbance in the peripheral metabolism of TRP that may result in a deficiency of the plasma L-TRP availability on which the central serotonin (5HT) synthesis closely depends. 5. In addition, the results suggest that the alteration in RBC L-TRP uptake is associated with loss of impulse control in schizophrenic patients.

Red blood cell triiodothyronine uptake in unipolar major depression : Effect of a chronic antidepressant treatment

The evolution of kinetic parameters (Vmax, maximal velocity, and Km, Michaelis constant) of red blood cell (RBC) triiodothyronine (L-T3) initial uptake was followed in 19 inpatients suffering from unipolar depression after 1 week (D7) and 4 weeks (D28) of a chronic administration of fluvoxamine, in relation with the clinical efficacy of the drug. In a drug-free state (DO), Vmax (in pmol/min/10(8) cells) and Km (in nM) were significantly increased in depressed patients (Vmax +/- S.D.= 1.02 +/- 0.29, p< 0.01 and Km +/- S.D.= 68.8 +/-15.4, p< 0.05; n=19) compared to healthy volunteers matched for age and sex (Vmax +/- S.D.= 0.82 +/- 0.15 and Km S.D.= 58.8 +/- 9.0; n= 19). When patients were dichotomized on the basis of their treatment response, responders had kinetic parameters significantly increased (Vmax +/-S.D.= 1.03 +/- 0.26, p< 0.01 and Km +/- S.D.= 71.7 +/- 18.7, p< 0.05, n= 10) compared to controls, whereas non-responders had not (Vmax +/- S.D.= 1.00 +/- 0.33, NS and Km +/- S.D.= 65.7 +/- 10.9, NS, n= 9). At D7, Vmax differed from the one of controls only in the responders (Vmax +/- S.D.= 1.03 +/-0.26, p< 0.01). In addition, the percentage of variation of the individual Vmax values during the first week of treatment was significantly lower in responders than in non-responders (deltaVmax(D7-D0) +/- S.D. in % = 10.7 +/- 6.0 and 22.0 +/- 11. 1, p< 0.05, respectively). At D28, kinetics of L-T3 uptake normalized only in the responders (Vmax +/- S.D.= 0.91 +/- 0.13, NS; Km+/-S.D.= 65.7 +/- 7.4, NS). The results indicate that both RBC L-T3 uptake at the pretreatment level and its change during the first week of fluvoxamine treatment were related to the further clinical response to the antidepressant. RBC L-T3 uptake seems to be a biological correlate of the depressive symptomatology since the disturbances disappear only with the clinical remission.

Secular trends in the age at onset of bipolar I disorder – Support for birth cohort effects from interational, multi-centre clinical observational studies

OBJECTIVEnTo examine any association of birth decade, sex and exposure to alcohol and/or substance use disorders (ASUD) with age at onset (AAO) of bipolar I disorder (BD-I).nnnMETHODSnUsing data from a representative clinical sample of 3896 BD-I cases recruited from 14 European countries, we examined AAO distributions in individuals born in consecutive birth decades. Cumulative probabilities with Mantel-Cox log-rank tests, pairwise comparisons and Odds Ratios (OR) with 95% confidence intervals (95% CI) were employed to analyze AAO according to birth decade, sex, and presence or absence of an ASUD.nnnRESULTSnIn the total sample, median AAO of BD-I decreased from about 41 years for those born in the 1930s to about 26 years for those born in the 1960s. In a sub-sample of 1247 individuals (selected to minimize confounding), AAO significantly decreased for males and females born in each consecutive decade between 1930 and 50 (OR: 0.65; 95% CI: 0.51, 0.81), and for cases with an ASUD as compared to without (OR: 0.77, 95% CI: 0.69, 0.87). The best fitting regression model identified an independent effect for each birth decade and an interaction between ASUD status and sex, with a consistently earlier AAO in males with an ASUD (OR: 0.79: 95% CI: 0.70, 0.91).nnnCONCLUSIONSnIn BD-I cases diagnosed according to internationally recognized criteria and recruited to pan-European clinical observational studies, the AAO distributions are compatible with a birth cohort effect. A potentially modifiable risk factor, namely ASUD status, was associated with the observed reduction in AAO, especially in males.

Effect of early trauma on the sleep quality of euthymic bipolar patients.

OBJECTIVEnPoor quality of sleep is frequent in euthymic bipolar patients and conveys worse clinical outcomes. We investigated the features of euthymic bipolar patients associated with poor sleep quality, with a focus on the effect of childhood trauma.nnnMETHODn493 euthymic patients with DSM-IV-defined bipolar disorders were recruited in FondaMental Advanced Centers of Expertize for Bipolar Disorders (FACE-BD) between 2009 and 2014. Clinical variables were recorded. Subjective sleep quality and history of childhood trauma were respectively measured by the Pittsburgh Sleep Quality Index (PSQI) and the Childhood Trauma Questionnaire (CTQ).nnnRESULTSnPoor sleepers were older, less professionally active, had significantly higher anxiety levels, took more anxiolytic drugs and did endorse more suicide attempts and suicidal ideas than good sleepers after adjusting for anxiety levels and age. Emotional abuse was associated with poor sleep quality after adjustment for BMI, age, professional activity, and bipolar disorders (BD) type (OR=1.83; 95% CI [1.30; 3.10]; p=0.02). However, this association was lost after adjustment for anxiety levels, anxiolytic treatment and suicide ideation/attempts.nnnLIMITATIONSnThe main limitation was the type of sleep assessment, which only measured the subjective part of sleep complaints.nnnCONCLUSIONnA history of emotional abuse might underlie sleep problems in many bipolar patients but anxiety seems to act as a confounding factor in this relationship. New studies are needed to elucidate the role of childhood maltreatment on poor sleep among bipolar patients.

1476 – Factors associated with lifetime antidepressant-induced mania in bipolar disorder patients

Introduction Antidepressants may induce manic or hypomanic episodes. The identification of predictors of antidepressant- induced mania (AIM) is essential to improve the management of bipolar disorder (BD). However, the rare studies on AIM are generally characterized by small sample sizes, varying definitions of AIM and heterogeneous groups of patients, thus leading to conflicting results. Objectives To compare a population of AIM(+) to AIM(-) patients in order to identify specific clinical factors associated with AIM. Methods All 252 participants met the DSM-IV criteria for BD. Only patients who reported AIM in the 90 days after the beginning of an antidepressant (with or without a mood stabilizer) were diagnosed as AIM (+) and those without any lifetime history of AIM despite lifetime antidepressant prescription were considered AIM (-). Sociodemographic and clinical factors were collected using the DIGS, ALS, AIS BIS and WURS. Results AIM(+) (N=74) and AIM(-) (N=178) patients did not differ significantly in terms of age, gender distribution, bipolar disorder duration and age of onset, ALS, BIS and WURS score. However, the rates of rapid cyclers, lifetime history of suicidal acts, alcohol use disorder and AIS score were significantly higher in the AIM(+)group. The type of polarity of onset was significantly different in both groups. Conclusions A history of rapid cycling, of suicidal acts and of alcohol use disorder could be considered as risk factors of AIM in BD. Patients with these factors could therefore be identified as a vulnerable subgroup prone to manic switch with antidepressant.