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.

Difference between evening and morning thyrotropin responses to protirelin in major depressive episode.

We studied the thyrotropin response to protirelin challenge (200 micrograms intravenously) at 8 am and at 11 pm after a minimum washout period of 10 days in 29 euthyroid inpatients who met DSM-III-R criteria for major depressive episode and 20 normal volunteer controls. The maximum increment in thyrotropin above baseline (delta thyrotropin) was significantly greater at 11 pm than at 8 am both in patients and in controls. However, the difference between 11 pm delta thyrotropin and 8 am delta thyrotropin (delta delta thyrotropin) was significantly lower in patients than in controls. The lower delta delta thyrotropin found in patients could not be explained by differences in age, body weight, sex, or thyroid functioning. In the overall population, delta delta thyrotropin correlated with circadian variables (ie, mesor and amplitude). With the use of a criterion of less than 3 mU/L to define a blunted delta delta thyrotropin, the diagnostic sensitivity was 89% and the specificity was 95%. We suggest that delta delta thyrotropin has the advantage of taking into account chronobiologic influences in the interpretation of the protirelin/thyrotropin challenge, and this may explain the improved diagnostic value derived from this measure in the diagnosis of major depressive episode.

Effect of antidepressant medication on morning and evening thyroid function tests during a major depressive episode.

BACKGROUND: This study sought to determine whether changes in thyroid function that may occur during antidepressant treatment are related to a direct effect of the drug on the thyroid axis or to a change in clinical state. METHODS: Morning and evening thyroid function was evaluated in 30 euthyroid inpatients who met DSM-IV criteria for major depressive episode, by determination of free triiodothyronine, free thyroxine, and thyrotropin levels before and after 8 AM and 11 PM protirelin challenges (200 micrograms intravenously), on the same day. Results at baseline were compared with those after 1 month of antidepressant treatment with either amitriptyline hydrochloride, fluoxetine hydrochloride, or toloxatone. RESULTS: Clinical efficacy and effects on thyroid function did not differ across the 3 antidepressant drugs. Compared with pretreatment values, significant reductions in basal serum 8 AM free thyroxine, 11 PM free thyroxine, and 8 AM free triiodothyronine levels and increases in 11 PM maximum increment in plasma thyrotropin level and the difference between 11 PM and 8 AM maximum increment in plasma thyrotropin values were observed in responders (n = 11) but not in partial responders (n = 6) or nonresponders (n = 13). Moreover, nonresponders exhibited lower pretreatment 11 PM thyrotropin values (basal and maximal increment above basal) than responders. CONCLUSIONS: The results suggest that (1) changes in thyroid function are related to clinical recovery rather than to a direct effect of the antidepressant drug and (2) patients with the lowest pretreatment evening thyrotropin secretion have the lowest rate of antidepressant response, and this may contribute to treatment resistance.

Influence of thyroid hormones on morning and evening TSH response to TRH in major depression.

The serum levels of thyroid hormones and thyrotropin (TSH) were evaluated before and after 8 PM and 11 PM thyrotropin-releasing hormone (TRH) challenges, on the same day, in 41 drug-free DSM-III-R euthyroid major depressed inpatients and 16 hospitalized controls. Depressed patients exhibited elevated circulating concentrations of thyroid hormones, which were associated with and may have contributed to the blunted TSH response to TRH. This was confirmed by: (a) higher basal levels (albeit not always statistically significant) of free triiodothyronine (FT3B) and free thyroxine (FT4B) at 8 AM and 11 PM in the depressed patient population compared with the controls; (b) lower basal levels of TSH in the depressed subjects (even though this was only statistically significant at the 11 PM sampling) compared with the controls; (c) blunted TSH response to TRH (delta TSH) in the depressed group (although this was only statistically significant at 11 PM) and blunted delta delta TSH values (differences between 11 PM-delta TSH and 8 AM-delta TSH).

All-night EEG spectral analysis as a tool for the prediction of clinical response to antidepressant treatment.

Earlier investigations have suggested that variables derived from quantified electroencephalographic (EEG) sleep analysis might predict good clinical response in an early phase of antidepressant treatment. In this report we evaluate the predictive value of all-night sleep EEG spectral analysis during the washout period before treatment. We compared the spectral EEG sleep profiles of major depressed inpatients divided into two groups according to an improvement > or = 50% on the Hamilton Rating Scale for Depression. Findings in this population demonstrate the presence of specific characteristics of the responder group compared with the nonresponder group. Delta band relative power was increased in the former group, while theta, alpha, and beta relative power were decreased. All the bands showed decrease in absolute power in the responder group. These results can be interpreted as enhanced sleep intensity in the responder group. All-night sleep EEG spectral variables are valid baseline markers of the functional differences between treatment responders and nonresponders and thus might permit prediction of clinical outcome.

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.

Temporal relationship between prolactin secretion and slow-wave electroencephalic activity during sleep.

It is well established that plasma prolactin (PRL) concentrations exhibit a sleep-dependent pattern, with the highest levels occurring during sleep and the lowest during waking. Still, controversy exists concerning an association between rapid eye movement (REM) and non-REM sleep cycles and plasma PRL pulses. These studies were all based on conventional scoring of sleep stages. In the present study, plasma PRL concentrations were analyzed at 10-minute intervals in 10 subjects during the night when sleeping. PRL secretory rates were calculated by a deconvolution procedure. Spectral parameters of sleep electroencephalographic (EEG) recordings were analyzed together with PRL secretion using cross-correlation. Slow-wave activity of the EEG and PRL secretion ran parallel in all individuals. Conversely, alpha and beta bands and the EEG mean frequency were inversely proportional to PRL secretion. In 9 of the 10 subjects studied, PRL secretion was concomitant with delta waves or lagged behind by 10-20 minutes, depending on subjects, with maximum cross-correlation coefficients ranging between 0.40 and 0.67. This temporal relationship between PRL secretion and delta waves was further assessed by a pulse-by-pulse analysis based on the calculation of probability levels after computer simulations. Nine of the 10 subjects displayed significant concomitance between delta wave activity and PRL secretory oscillations. These results demonstrate that PRL secretion during sleep is coupled to delta waves in young healthy men.

A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves.

The existence of a relationship between growth hormone (GH) release and slow-wave sleep (SWS), often studied in the past using conventional scoring of sleep stages, remains controversial. In the present study, this relationship was reevaluated by spectral analysis of the sleep electroencephalogram (EEG) and deconvolution analysis of the plasma GH concentrations during normal nocturnal sleep and after enrichment in SWS by means of ritanserin, a selective 5-HT2 receptor antagonist. Eight healthy male subjects each participated in two randomized night studies after having received either a placebo or a 5-mg dose of ritanserin. They were subjected to 8 hours of polysomnography, including spectral analysis of the sleep EEG. Plasma GH levels were measured at 10-minute intervals. The mean delta absolute power and the mean GH secretory rates were significantly higher under ritanserin than under placebo for the first 3 hours after sleep onset (+24% and +29%, respectively). Their nocturnal profiles were significantly and positively correlated in all subjects (average r = 0.710 under placebo, 0.567 under ritanserin; p < 0.0001 in both cases). GH secretory pulses were found to be coincident with delta activity peaks in both directions. The amount of GH secreted during significant GH pulses was correlated with the amount of concomitant delta wave activity (r = 0.803 under placebo, r = 0.764 under ritanserin, p < 0.0001). Similarly, the amount of delta wave activity found during delta wave peaks was correlated with the amount of GH secreted concomitantly (r = 0.715 under placebo, r = 0.723 under ritanserin: p < 0.0001). These results demonstrate a close temporal and quantitative relationship between GH secretion and delta wave activity, which may be evidence of common stimulatory mechanisms.

First-night effect in normal subjects and psychiatric inpatients.

The goal of the present study was to evaluate the first-night effect in psychiatric inpatients using large subject samples (n > 30) in order to obtain a good statistical evaluation. Thirty-two normal subjects and 94 psychiatric inpatients (38 depressives and 56 insomniacs) were studied for three consecutive nights in the hospital sleep laboratory. Our results showed clearly that there was a first-night effect in normal subjects, similar to that reported in previously published data, characterized by a longer rapid eye movement (REM) sleep latency (p < 0.05), increased wakefulness (p < 0.01) and total sleep time (p < 0.02) and a decreased sleep efficiency (p < 0.01). REM sleep latency and stage REM in the first third of the night were still altered in the second night. Both clinical groups had a less marked first-night effect than normal subjects, showing alterations only observed in REM sleep (p < 0.01) (decreased REM sleep, longer REM sleep latency, increased REM sleep gravity center). However, the first-night effect was more pronounced in insomniacs than in depressed patients. No statistical differences between the second and third nights' recordings were found in sleep parameters. It is suggested that first-night data should not be simply discarded but could be used in subsequent analyses.

Sleep stage scoring using the neural network model: comparison between visual and automatic analysis in normal subjects and patients.

In this paper, we compare and analyze the results from automatic analysis and visual scoring of nocturnal sleep recordings. The validation is based on a sleep recording set of 60 subjects (33 males and 27 females), consisting of three groups: 20 normal controls subjects, 20 depressed patients and 20 insomniac patients treated with a benzodiazepine. The inter-expert variability estimated from these 60 recordings (61,949 epochs) indicated an average agreement rate of 87.5% between two experts on the basis of 30-second epochs. The automatic scoring system, compared in the same way with one expert, achieved an average agreement rate of 82.3%, without expert supervision. By adding expert supervision for ambiguous and unknown epochs, detected by computation of an uncertainty index and unknown rejection, the automatic/expert agreement grew from 82.3% to 90%, with supervision over only 20% of the night. Bearing in mind the composition and the size of the test sample, the automated sleep staging system achieved a satisfactory performance level and may be considered a useful alternative to visual sleep stage scoring for large-scale investigations of human sleep.

Changes in EEG power density during sleep laboratory adaptation.

First- and second-night effects on the electroencephalogram (EEG) were investigated by means of polygraphic sleep recordings and all-night spectral analysis. Eighteen normal subjects were studied for three consecutive nights in a hospital sleep laboratory. Visual sleep scoring showed that there was a first-night effect in normal subjects similar to that reported previously [increased wakefulness; decreased total sleep time, sleep efficiency, and rapid eye movement (REM) sleep]. Spectral analysis of the sleep EEG revealed important changes, most of which occurred in REM sleep. Increased delta, theta, and beta1 power densities accompanied by decreased mean frequency were seen in REM sleep in the second night. On the basis of REM sleep deprivation results previously published, our data suggest that the second night could be affected by partial REM sleep deprivation that occurred in the first night. Delta and theta power density values decreased in the first non-rapid eye movement episode of nights 1 and 2; this could result from increased REM sleep pressure. The overall consistency of spectral data in the first and second night with REM sleep findings derived from visual scoring in the first night lends further support to this hypothesis. The sleep disturbance experienced during the first night in a sleep laboratory may be a useful and valid model of transient insomnia. Therefore, we conclude that data from all nights recorded should be included in assessing a subject's sleep.

Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: tentative association between B37 and schizophrenia.

We have genotyped unrelated French Alsatian schizophrenic and bipolar I disorder (BPD) patients and matched controls for the polymorphic CAG repeats within the genes for spinocerebellar ataxia type 1 (SCA1) and dentatorubral-pallidoluysian atrophy (B37), in order to test their possible involvement in these disorders. No alleles with abnormally expanded repeats were found in either gene in patients and controls. Differences in allele and genotype frequencies for the SCA1 CAG repeat between patients and controls were not significant, thus providing no support for its role as a possible positional candidate gene for schizophrenia and BPD in our patients. Chi square testing revealed a significant result (P = 0.019) for an association between the B37 CAG repeat on chromosome 12p and schizophrenia. This result was more significant when only schizophrenics with a positive family history were compared with controls (P = 0.0001). The frequencies of alleles with 14, 12, and 15 CAG repeats differed the most, respectively, between schizophrenics and controls. When choosing the median of the B37 allele distribution (15 CAG repeats) as a threshold, there were significantly more controls than schizophrenics in the group with longer alleles (15 or more repeats) and more schizophrenics with shorter alleles (P = 0.002 by Fisher exact test). No particular genotype was associated with schizophrenia. This result possibly indicates linkage disequilibrium with another locus on chromosome 12p and therefore deserves further attention. No association was found between the B37 CAG repeat and patients with BPD.

Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders.

In a population-based association study, we tested the hypothesis that allelic variants of the human serotonin transporter (5-HTT) gene confer susceptibility to mood disorders. Both a biallelic repeat polymorphism in the 5' promotor region that differentially modulates gene expression and a second intron variable-number-tandem-repeat (VNTR) marker were genotyped in 294 controls and 115 patients with mood disorders. Subjects were of West European descent and included 36 patients with major depressive disorder (MDD) and 79 patients with bipolar I disorder (BD). No significant differences in genotype or allele frequencies were found at either locus between controls and combined patients, nor between controls and MDD or BD patients separately. Thus, our data do not support the association between depressive disorder and a nine-repeat allelic variant of the 5-HTT VNTR marker recently reported by Ogilvie et al. (Lancet 347:731-733, 1996). More importantly, no association between alleles conveying functional differences in 5-HTT gene expression and MDD or BD could be found. Taken together, our data suggest that the 5-HTT gene is not commonly involved in the susceptibility to mood disorders.

Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distribution of the Msp I and Bal I genotypes were not independent in 297 individuals (chi 2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (chi 2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls (chi 2 = 5.3, df = 1, P = 0.02) and found more important in mal than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (chi 2 = 0.06, df = 1, P = 0.80, chi 2 = 0.22, df = 1, P = 0.90 and chi 2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms.

Multihormonal responses to apomorphine in mental illness.

The neuroendocrine responses to subcutaneous (SC) administration of the dopamine (DA) agonist apomorphine (APO) hydrochloride (0.75 mg) were studied in a large group of subjects: 110 drug-free inpatients with either DSM-III-R schizophrenia (SCZ, n = 46), schizoaffective disorder (SAD, n = 14), or major depressive episode (MDE, n = 50), plus 18 hospitalized controls. Compared to a saline test, APO induced a significant increase of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol (COR) release and a decrease in prolactin (PRL) secretion. No change in thyrotropin (TSH) levels was observed. In the total sample the extents of ACTH, COR and GH responses were correlated, but in the group of 88 subjects who exhibit a normal GH stimulation this correlation disappeared. This discrepancy suggests that APO-induced ACTH and COR stimulation may be mediated by pathways different from those mediating GH stimulation. According to diagnostical categories, we found significant lower ACTH and COR stimulation in the schizophrenic group and in patients with SAD, compared with that among controls or depressed patients. We found also a significant difference between subgroups of schizophrenic patients. These results agree with the hypothesis that different aspects of psychosis might involve different subtypes of DA-receptors with different localizations and sensitivities.

HPA axis dysfunction in depression: correlation with monoamine system abnormalities.

Abnormality of the hypothalamic-pituitary-adrenal (HPA) axis has been one of the most consistently demonstrated biological markers of depressive disorder. It has also been proposed that abnormality of monoamine function plays a role in the pathogenesis of the disorder. In order to examine the interrelationships of the HPA axis with the dopaminergic, noradrenergic, and serotoninergic systems, we studied, in 52 medication-free inpatients with DSM-IV nonpsychotic major depressive disorder, the relationship between dexamethasone suppression test (DST) status and a series of multihormonal responses to apomorphine (APO), clonidine (CLO), and D-fenfluramine (FEN) tests. DST nonsuppressors did not present any difference compared with suppressors in growth hormone (GH) and cortisol stimulation by APO suggesting that a chronic elevation of cortisol did not lead to an alteration of dopaminergic activity in this population of nonpsychotic depressed inpatients. Cortisol and prolactin responses to FEN were comparable in nonsuppressors and in suppressors. In contrast, GH response to CLO was lower in DST nonsuppressors than in suppressors (p < .03), suggesting that the HPA abnormality indicated by a positive DST may be related to alpha 2-adrenoreceptor dysfunction.

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.

Thyroid axis activity and serotonin function in major depressive episode.

Recent studies in depression have reported alterations in both hypothalamic-pituitary-thyroid (HPT) axis activity and serotonin (5-HT) function; however, the functional relationships between the two systems have not been well defined in patients with major depressive episode. Thyrotropin (TSH) response to 0800 and 2300 h protirelin (TRH) challenges, and adrenocorticotropic hormone (ACTH), cortisol, and prolactin (PRL) responses to D-fenfluramine (D-FEN), a specific 5-HT releasing/uptake-inhibiting agent, were examined in 60 drug-free DSM-IV major depressed inpatients and 20 hospitalized controls. Compared with controls, patients showed lower basal serum 2300 h TSH, 2300 h maximum increment in serum TSH above baseline (delta TSH) and difference between 2300 h delta TSH and 0800 h delta TSH (delta delta TSH) levels. The hormonal responses to D-FEN (i.e. delta ACTH, delta cortisol and delta PRL) were interrelated. No significant difference in basal and post-D-FEN ACTH, cortisol or PRL values were found between controls and patients. A negative relationship between hormonal responses to D-FEN and 2300 h delta TSH and delta delta TSH values was observed in the depressed group. When patients were classified on the basis of their delta TSH test status, patients with reduced delta delta TSH values (i.e. with HPT axis abnormality) had hormonal D-FEN responses comparable to those of controls. Patients with normal delta delta TSH values (i.e. without HPT axis abnormality) showed lower ACTH, cortisol and PRL responses to D-FEN than controls and patients with abnormal delta delta TSH values. These results suggest that: (1) pathophysiological mechanisms other than 5-HT dysregulation may be involved in TSH blunting in major depressed patients; (2) 5-HT function is reduced in some depressed patients, especially those without HPT axis abnormality; and (3) HPT dysregulation may be regarded as a compensatory mechanism for diminished central 5-HT activity.

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.

A double-blind comparison of moclobemide and amineptine in the treatment of depressed out-patients.

A randomized, double-blind, multicentre study was performed to compare the effects of moclobemide and amineptine in the treatment of endogenous depression in out-patients. Ninety patients received moclobemide, 450 mg/day and 94 received amineptine 200 mg/day in two parallel groups, over a trial period of 8 weeks. At the end of 4 weeks doses could be reduced to 300 mg/day, moclobemide and 100 mg/day, amineptine if required. All evaluated patients showed a significant clinical improvement during treatment, but no significant difference occurred between the groups. When patients were asked to assess the benefit of their treatment, 76% thought their condition had improved following moclobemide therapy, compared to 53% of those receiving amineptine. Both drugs were well tolerated, and over 60% of patients reported no side-effects. Moclobemide appeared to be as effective as amineptine in the treatment of these patients, and was significantly better tolerated.