A positron emission tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A receptor occupancy in patients treated with cyamemazine (Tercian).

RATIONALE: Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT(2A) receptors, which was fourfold higher than its affinity for dopamine D(2) receptors (Hameg et al. 2003). OBJECTIVES: The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian. METHODS: Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan. RESULTS: Cyamemazine induced near saturation of 5-HT(2A) receptors (RO=62.1-98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D(2) receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2-74.9%). The effective plasma level of cyamemazine leading to 50% of D(2) receptor occupancy was fourfold higher than that for 5-HT(2A) receptors. Accordingly, individual 5-HT(2A)/D(2) RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale. CONCLUSION: This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT(2A) receptors compared to dopamine D(2) receptors. In the dose range 37.5-300 mg, levels of dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.

Restless legs syndrome and low brain iron levels in patients with haemochromatosis.

Regional brain iron levels of two patients with haemochromatosis and severe restless legs syndrome (RLS) were assessed using R2' magnetic resonance imaging (MRI) sequences in both patients and in nine healthy controls. R2' relaxation rates in the patients were decreased in the substantia nigra, red nucleus, and pallidum when compared with the controls. These results indicate that local brain iron deficiency may occur in patients with haemochromatosis and suggest a role for brain iron metabolism in the pathophysiology of RLS.

Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo.

Fluorine magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI) and proton anatomical magnetic resonance imaging (1H MRI) were performed on brains and lower extremities of six subjects in vivo concurrently with HPLC of serum to investigate tissue and plasma drug localization and withdrawal kinetics in humans treated with fluvoxamine or fluoxetine. 19F MRS signal was unexpectedly detected in the lower extremities months after complete disappearance of signal from plasma and brain. MRSI suggested that the lower extremity fluvoxamine signal originated mainly from bone marrow. Results suggest long-term sequestration of these drugs or their metabolites mainly in bone marrow and possibly in surrounding tissue and demonstrate the usefulness of MRS to reveal drug-trapping compartments in the body.

[Development of compounds active in insomnia: recent developments and methodological aspects]. / Développement de molécules actives dans l'insomnie: actualités et aspects méthodologiques.

Most pharmacotherapeutic treatments designed to treat insomnia target GABAergic activity globally in the brain. Development of new molecules having a more specific activity pathway should improve treatment efficacy and acceptance. Both subjective and objective criteria are needed to study drug efficacy. Data regarding drug effects on polysomnographic recordings are mandatory for the development of hypnotics. Whether the drug-induced sleep is comparable to normal sleep is tackled with the spectral analysis of the sleep EEG. Residual drug effects are assessed with a package of psychomotor and neurocognitive tests, and with the driving simulator test Clinical studies investigating drug efficacy and tolerability have to be conducted on large groups of patients carefully selected using polysomnographic recordings. Our knowledge about sleep will undoubtedly soon become available for treatment of insomnia.

[Personality changes in opioid-dependent subjects in a methadone maintenance treatment program]. / Changements psychologiques au cours d'un traitement de substitution de méthadone, mesurés par l'Inventaire de Personnalité d'Eysenck.

Personality disorders and particularly antisocial personality disorders (APD) are quite frequent in opioid-dependent subjects. They show various personality traits: high neuroticism, high impulsivity, higher extraversion than the general population. Previous studies have reported that some but not all personality traits improved with treatment. In a previous study, we found a low rate of APD in a French population of opioid-dependent subjects. For this reason, we evaluated personality traits at intake and during maintenance treatment with methadone. Methods - The form A of the Eysenck Personality Inventory (EPI) was given to opioid addicts at intake and after 6 and 12 months of methadone treatment. Results - 134 subjects (96 males and 38 females) took the test at intake, 60 completed 12 months of treatment. After 12 months, the EPI Neuroticism (N) and the Extraversion-introversion (E) scale scores decreased significantly. The N score improved in the first 6 months, while the E score improved only during the second 6 months of treatment. Compared to a reference group of French normal controls, male and female opioid addicts showed high N and E scores. Demographic data and EPI scores of patients who stayed in treatment for 12 months did not differ significantly from those of dropouts (n=23). Patients with a history of suicide attempts (SA) started to use heroin at an earlier age and they showed a higher E score and a tendency for a higher N score at intake. Discussion - The two personality dimensions of the EPI changed during MMT, and the N score converged towards the score of normal controls. Opioid addicts differ from normal controls mostly in their N score. The EPI did not help to differentiate 12-month completers from dropouts. Higher E scores in patients with an SA history might reflect a higher impulsivity, which has been linked to suicidality in other patient groups.

[Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatonin- agonist and selective 5HT2c receptors antagonist, in the treatment of major depressive disorders]. / Etude pilote comparant en aveugle l'effet thérapeutique de deux doses d'agomélatine, agoniste des récepteurs de la mélatonine et antagoniste des récepteurs 5HT2C, chez 30 patients présentant un épisode dépressif majeur.

RATIONALE AND METHOD: Two doses of agomelatine (S-20098), a novel potential antidepressant drug with a new pharmacological profile (melatonin agonist and selective 5HT2C antagonist), were compared in a double-blind, randomised, pilot study in order to estimate the antidepressant activity shown in preclinical data. Inpatients suffering from major depressive disorder (DSM III-R criteria) and presenting a minimal score of 25 for MADRS were selected at D-7. After one week of run-in placebo treatment, included patients received one evening dose of agomelatine (either 5 or 100 mg) for 4 to 8 weeks. Hospitalization was required at least for the first 3 weeks. Patients presenting a satisfying response to treatment (MADRS total score < 15 or decrease > or = 40% from inclusion score) could be treated as outpatients. A follow up of 2 weeks was performed after stopping the treatment. The total duration of the treatment period could vary, according to investigator's decision, between 7 and 11 weeks. Evaluation criteria included MADRS, HAMD-17, HAM-A, CGI and AMDP 5 at D0, D7, D14 and D28, and, when applicable, at D35, D42, D49 and D56. Safety evaluations included recording of adverse events, ECG monitoring and biology. RESULTS: Thirty inpatients were selected and 28 included (14 per group). There was no major difference between groups at inclusion, neither for demographic nor evaluation criteria. One patient of each group was excluded of the ITT analysis; 19 patients completed the mandatory period up to D28: 10 in the 5 mg group and 9 in the 100 mg group; 10 patients (5 in each group) carried on the study during the optional period, up to D56 for 7 out of them (4 in the 5 mg group, 3 in the 100 mg group). Efficacy criteria showed a significant improvement in both groups, with highly significant within group evolutions (p < 0.001 whatever the criteria) and without significant difference between groups. However, better results were observed in the 5 mg group compared to the 100 mg group. Total MADRS scores then decreased from 30.7 +/- 3.5 to 14.8 +/- 6.4 in the 5 mg group vs a decrease from 31.6 +/- 4.7 to 18.6 +/- 14.8 in the 100 mg group. Furthermore, significant improvement between D14 and D28 visits were only seen in the 5 mg group. Analysis of somatic complaints (AMDP 5) showed with both treatments a strong decrease of symptoms during the study, especially for items related to sleep disorders (difficulties in falling asleep, interrupted sleep, shortened sleep, early wakening and drowsiness). Acceptability was good for both doses of agomelatine. However, there were slightly more emergent adverse events and severe treatment-related adverse events in the 100 mg group. No modifications of cardio-vascular parameters nor biological abnormalities were observed in both groups. CONCLUSION: Preliminary clinical data with agomelatine confirm the potential antidepressant effect in accordance with positive preclinical results. There was no significant difference between 5 and 100 mg, both for efficacy and for safety. However, the data suggest that 5 mg could be a dose at least as effective and slightly better tolerated than 100 mg. Further double-blind controlled studies versus active comparators and placebo are required in order to confirm these results.

Characterization of the CNS effects of naftidrofuryl (Praxilène) by quantitative EEG and functional MRI: a study in healthy elderly subjects.

In the present study, we investigated the effects of a single and a repeated (5 days) administration of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor having neuroprotective properties, on functional brain physiology in male healthy elderly subjects, using quantitative electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twelve subjects aged 60 +/- 3.8 years completed the quantitative EEG study, where the effects of 400 and 600 mg were assessed, and 12 other subjects (aged 56 +/- 4.7 years) completed the fMRI study, where the effect of 400 mg was assessed on the brain activation induced by the continuous performance test (CPT). Naftidrofuryl induced a transient reduction in alpha activity followed by a specific synchronisation of the 9.5- to 11-Hz EEG activity most pronounced after repeated administration. Such regimen also increased the CPT-induced brain activation visualized by way of fMRI. The results of the present study can be interpreted at the functional level that naftidrofuryl induced an improved level of vigilance or an increased capacity of alertness in healthy elderly subjects.

Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients.

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.

[The impact of substitution treatment by methadone among opiate-dependent subjects evaluated by Addiction Severity Index and by urine tests]. / Impact d'un traitement de substitution par méthadone sur des sujets dépendants aux opiacés évalué par l'Addiction Severity Index et des contrôles urinaires.

Methadone maintenance treatment (MMT) has been evaluated in the United States and in a few other countries. MMT has been developed in France since 1995, and over 5 000 patients receive this treatment. However no French study has yet been published on the efficacy of MMT as assessed by a validated scale. Retention in treatment for one year has been considered as a threshold to define maintenance of treatment benefits after discharge from a methadone program; determination of retention predictors is important. Over a three year period, we evaluated patients at admission and during treatment using the Addiction Severity Index (ASI), and urine drug screening was performed weekly; 95 patients (66 males and 29 females) were evaluated at intake. Their mean age was 30.2 5.5, and they had used opioids for a mean of 10.6 5.7 years. Their ASI severity scores for drugs were over 5, showing a clear need for treatment. Female patients differed from males only in the employment-finances ASI score; 43 patients completed at least one year of treatment, after which their drug and legal composite scores significantly improved. No significant changes in their consumption of cocaine, alcohol, benzodiazepines or cannabis were found, but they smoked fewer cigarettes at 12 months. Demographics, ASI severity scores, and history of suicide attempts did not differentiate one-year completers from dropouts (n=16). However, dropouts had used more buprenorphine and less methadone in the 30 days preceding their admission, and they received a lower dose of methadone during treatment. Our population is comparable to other French MMT populations; they enter treatment after a long history of opioid dependence. The improvement found on the ASI composite scores is also similar to the improvement described in other international studies. Dropouts in our study seem to be more treatment-resistant patients, in the sense that they had used more buprenorphine before intake and were not stabilized with it; and they may have had a more negative attitude towards methadone.

[Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5HT2C receptors antagonist, in the treatment of major depressive disorders]. / Etude pilote comparant en aveugle l'effet thérapeutique de deux doses d'agomélatine - agoniste des récepteurs de la mélatonine et antagoniste des récepteurs 5HT2c - chez 30 patients.

Rational and method - Two doses of agomelatine (S-20098), a novel potential antidepressant drug with a new pharmacological profile (melatonin agonist and selective 5HT2C antagonist -MASSA), were compared in a double-blind, randomised, pilot study in order to estimate the antidepressant activity shown in preclinical data. Inpatients suffering from major depressive disorder (DSM III-R criteria) and presenting a minimal score of 25 for MADRS were selected at D -7. After one week of run-in placebo treatment, included patients received one evening dose of agomelatine (either 5 or 100 mg) for 4 to 8 weeks. Hospitalization was required at least for the first 3 weeks. Patients presenting a satisfying response to treatment (MADRS total score<15 or decrease 40% from inclusion score) could be treated as outpatients. A follow up of 2 weeks was performed after stopping the treatment. The total duration of the treatment period could vary, according to investigator's decision, between 7 and 11 weeks. Evaluation criteria included MADRS, HAMD-17, HAM-A, CGI and AMDP 5 at D0, D7, D14 and D28, and, when applicable, at D35, D42, D49 and D56. Safety evaluations included recording of adverse events, ECG monitoring and biology. Results - Thirty inpatients were selected and 28 included (14 per group). There was no major difference between groups at inclusion, neither for demographic nor evaluation criteria. One patient of each group was excluded of the ITT analysis; 19 patients completed the mandatory period up to D28: 10 in the 5 mg group and 9 in the 100 mg group; 10 patients (5 in each group) carried on the study during the optional period, up to D56 for 7 out of them (4 in the 5 mg group, 3 in the 100 mg group). Efficacy criteria showed a significant improvement in both groups, with highly significant within group evolutions (p<0.001 whatever the criteria) and without significant difference between groups. However, better results were observed in the 5 mg group compared to the 100 mg group. Total MADRS scores then decreased from 30.7 3.5 to 14.8 6.4 in the 5 mg group vs a decrease from 31.6 4.7 to 18.6 14.8 in the 100 mg group. Furthermore, significant improvement between D14 and D28 visits were only seen in the 5 mg group. Analysis of somatic complaints (AMDP 5) showed with both treatment a strong decrease of symptoms during the study, especially for items related to sleep disorders (difficulties for falling asleep, interrupted sleep, shortened sleep, early wakening and drowsiness). Acceptability was good for both doses of agomelatine. However, there were slightly more emergent adverse events and severe treatment-related adverse event in the 100 mg group. No modifications of cardio-vascular parameters nor biological abnormalities were observed in both groups. Conclusion - Preliminary clinical data with agomelatine confirm the potential antidepressant effect in accordance with positive preclinical results. There was no significant difference between 5 and 100 mg, both for efficacy and for safety. However, the data suggest that 5 mg could be a at least as effective and slightly better tolerated dose than 100 mg. Further double-blind controlled studies versus active comparators and placebo are required in order to confirm these results.

Effects of the selective activation of 5-HT3 receptors on sleep: a polysomnographic study in healthy volunteers.

The respective role of various classes of central serotonin (5-HT) receptors in the regulation of sleep-wakefulness cycles has been the subject of many studies. Notably, it has been reported that 5-HT1A/B receptors are involved in the regulation of rapid eye movement sleep (REMS) and that 5-HT2A/C receptors participate in the control of slow wave sleep (SWS), but the role of 5-HT3 receptors is less well characterised. In this study we investigated the effects of SR 57227A, a potent and selective 5-HT3 agonist, on the sleep EEG of normal young male volunteers. SR 57227A (2.5, 5, 10, 20, 40 mg o.d. and 20 mg b.i.d.) or placebo were administered during 7 consecutive days in seven groups of ten subjects using a parallel group design. Sleep EEG recordings were performed on days 6 and 7 after an habituation session. SR 57227A produced a dose-dependent shift of REMS toward the end of the night without changing REMS and SWS duration nor altering sleep continuity. It suggests a role for the 5-HT3 receptor in the human sleep-wakefulness cycle and particularly in REMS regulation.

Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour.

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.

Morning and evening TSH response to TRH and sleep EEG disturbances in major depressive disorder.

1. The aim of this study was to investigate hypothalamo-pituitary-thyroid axis (HPTA) functioning and sleep EEG disturbances in major depressive disorder. 2. Thyroid function was evaluated by determination of TSH levels before and after 8 AM and 11 PM TRH administration on the same day in a sample of 113 consecutively-admitted DSM-IV major depressed inpatients (72 females aged 44.3 +/- 13.0 and 41 males aged 45.7 +/- 10.7) that underwent sleep EEG recordings. 3. A blunted TSH response occurred in 15.9% for 8 AM deltaTSH (maximum increment above baseline at the 8 AM TRH challenge), in 39.8% for 11 PM deltaTSH and in 77% for deltadeltaTSH (difference between 11 PM deltaTSH and 8 AM deltaTSH). A negative correlation between deltadeltaTSH and duration of awakenings after sleep onset, and a shorter sleep onset latency in patients with a blunted 11 PM deltaTSH were found, but these two significant relationships disappeared after controlling for the effects of gender and age. 4. The present findings do not support the hypothesis that, in major depression, HPTA dysfunctioning, as reflected in TSH response to TRH, may be related to sleep EEG disturbances.

Noradrenergic dysfunction and antidepressant treatment response.

The purpose of this study was to investigate differences in outcome following treatment with two different antidepressants in depressed patients according to their pretreatment hormonal response to clonidine. In all, 62 drug-free DSM-IV recurrent major depressed patients and 20 normal controls were studied. Patients were subsequently treated for 4 weeks with fluoxetine (n=28), or amitriptyline (n=34), and were then classified as responders or nonresponders according to their final Hamilton depression scale score. Compared to controls, depressed patients showed lower GH response to CLO (DeltaGH) (P<0.0002). One control (5%) and 35 depressed patients (56%) had blunted DeltaGH values. The efficacy of the two antidepressants was not significantly different: 15 patients responded to AMI (44%), seven patients responded to FLUOX (25%) (P>0.15). However, in the subgroup of patients with blunted DeltaGH levels, the rate of responders was higher for AMI (11/21) compared to FLUOX (1/14) treated patients (P<0.01). These results suggest that in depressed patients a blunted GH response to CLO could predict antidepressant response.

Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy.

This investigation of fluvoxamine and fluoxetine-norfluoxetine distributions in vivo at steady-state and of quantitative kinetics in brain and plasma after drug therapy interruption was performed by fluorine nuclear magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI), and plasma HPLC on 12 subjects treated for depression. MRSI suggests a homogeneous distribution of 19F MRS visible fluvoxamine mainly in brain. Fluvoxamine steady-state brain concentrations (12 +/- 5 microM; n = 13) and brain-to-plasma concentration ratios (10 +/- 2; n = 12) were similar to those of combined fluoxetine-norfluoxetine (CF-norfluoxetine) (13 +/- 6 microM; n = 4 and 10 +/- 6; n = 4). Fluvoxamine brain elimination half-life (79 +/- 24 hours; n = 4) was significantly shorter than that of CF-norfluoxetine (382 +/- 48 hours; n = 2). Fluvoxamine brain-to-plasma-half-life-ratio was 2.2 +/- 0.3 (n = 4), contrarily to CF-norfluoxetine (1.0 +/- 0.3; n = 2). This study shows that quantitative pharmacokinetics in target organs by 19F MRS in vivo should prove useful for understanding and investigating outcome of treatment modifications and side effects.

Multihormonal responses to clonidine in patients with affective and psychotic symptoms.

The neuroendocrine responses to the alpha(2)-adrenoreceptor agonist clonidine (CLO) (0.35 mg if body weight <65 kg or 0.375 mg if body weight> or =65 kg, PO) were studied in a large group of subjects: 134 drug-free inpatients--with either DSM-IV schizophrenia (SCZ, n=31), schizoaffective disorder (SAD, n=16), or major depressive episode (MDE, n=87) - and 22 hospitalized controls (HCs). Comparison with a previous placebo test performed in a subgroup of 92 subjects (46 MDEs, 20 SCZs, 8 SADs, and 18 HCs) showed that CLO induced a significant increase of growth hormone, prolactin (PRL) and thyrotropin (TSH) levels but no significant change in adrenocorticotropin and cortisol release. According to diagnostic categories, we found significantly lower GH stimulation in MDEs and in SADs compared to HCs or to SCZs. In addition, we found significantly lower CLO induced PRL and TSH stimulations in paranoid SCZ patients compared to controls and disorganized SCZ patients. Taken together, these results suggest a hyposensitivity of noradrenergic alpha(2)-receptors in patients with affective symptoms.

Dopaminergic function and the cortisol response to dexamethasone in psychotic depression.

1. It has been hypothesized that psychotic symptoms in depression may be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity. 2. To test this hypothesis, the authors examined the cortisol response to dexamethasone suppression test (DST, 1 mg orally) and multihormonal responses to apomorphine (APO, 0.75 mg s.c.)--a dopamine agonist--in 150 drug-free hospitalized patients with DSM-IV major depressive episode with psychotic features (MDEP, n=35), major depressive episode without psychotic features (MDE, n=74), or schizophrenia paranoid type (SCZ, n=41), and 27 hospitalized healthy controls (HCs). 3. MDEPs showed increased activity of the HPA system (i.e. higher post-DST cortisol levels) than HCs, SCZs and MDEs. However, there were no differences in adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH) responses to APO between MDEPs and MDEs and HCs. On the other hand, SCZs showed lower APO-induced ACTH stimulation and a higher rate of blunted GH than HCs, MDEs and MDEPs, suggesting a functional alteration of the hypothalamic dopamine receptors in SCZs. 4. In the total sample and in each diagnostic group, DST suppressors and non-suppressors showed no differences in hormonal responses to APO. 5. These results suggest a lack of causal link between HPA axis hyperactivity and dopamine dysregulation. In contrast to schizophrenia, psychotic symptoms in depression seem not to be related to dopamine function dysregulation.

Prolactin response to D-fenfluramine and suicidal behavior in depressed patients.

Previous studies of the prolactin response to D-fenfluramine in depressed patients have yielded inconsistent results. This may be because they did not address the question of suicidality. We carried out this study to test the hypothesis that lower prolactin response to D-fenfluramine is more closely associated with suicidal behavior than with depression itself. A D-fenfluramine test was performed in a sample of 18 healthy control subjects and in 85 drug-free inpatients with a DSM-III-R diagnosis of major depressive episode (49 with a history of suicide attempt, 36 without). Depressed inpatients with a history of suicide attempt showed a significantly lower prolactin response to D-fenfluramine compared to depressed inpatients without such a history and compared to control subjects. Healthy control subjects and depressed inpatients without a history of suicide attempt showed comparable levels of prolactin after D-fenfluramine. Time elapsed since suicide attempt did not influence prolactin level (baseline or post-stimulation). Results show that in our depressed drug-free inpatient sample, prolactin response to D-fenfluramine seems to be a marker of suicidality, but not of depression itself. We suggest that it is a trait marker of suicidality.

Serotonergic and noradrenergic function in depression: clinical correlates.

The present study was conducted in order to investigate the relationships between central noradrenergic (NA) and serotonergic (5-HT) function and clinical characteristics of a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We measured growth hormone response (ΔGH) to clonidine (CLO) (an α2 NA agonist), as an index of central NA function, and prolactin response (APRL) to d-fenfluramine (d-FEN) (a specific 5-HT releaser/uptake inhibitor), as an index of central 5-HT function, in 53 medication-free depressed inpatients. On the basis of their CLO and d-FEN test responses, patients were classified into 4 groups. Group 1 (blunted ΔPRL(d-FEN) alone [11 %]) was characterized by a recent violent suicide attempt, a high degree of medical damage, and mild anxiety. Group 2 (blunted ΔGH(CLO) alone [32%]) was characterized by an absence of a history of suicide attempt and by severe anxiety. Group 3 (combination of blunted ΔGH(CLO) and APRL(d-FEN) [18%]) was characterized by a history of suicide attempts, total duration of the illness of over W years, age over 40 years, and more than 3 previous hospitalizations. Group 4 (no abnormality [39%]) had no specific clinical profile. These results suggest that, in depression, specific psychopathological features may be linked to 5-HT and/or NA dysfunction. However, our results also suggest that NA and/or 5-HT dysfunction are less likely to be the primary cause of mood disorders but are more indicative of failure of compensatory mechanisms involved in affective homeostatic processes.