Combined treatment with imipramine and metyrapone induces hippocampal and cortical brain-derived neurotrophic factor gene expression in rats

The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. Recently it was shown that joint administration of imipramine (IMI) and metyrapone (MET), an inhibitor of glucocorticoid synthesis, produced a more potent "antidepressant" effect in the forced swimming test than did treatment with either drug alone. Our studies also showed that co-administration of IMI and MET to drug-resistant, unipolar depressed patients effected a clinical improvement. In addition, recent studies indicated a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present research we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and MET (50 mg/kg), given separately or jointly (twice daily for 14 day), on the BDNF mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last dose of IMI and MET. The obtained results showed that in the hippocampus IMI (10 mg/kg) and cerebral cortex IMI (5 mg/kg) and MET (50 mg/kg) significantly elevated the BDNF mRNA level. Joint administration of IMI (10 mg/kg) and MET (50 mg/kg) induced a more potent increase BDNF gene expression in both the examined brain regions (compared to the treatment with either drug alone). Moreover, the obtained results suggested that BDNF may be involved in the mechanism of the synergistic antidepressant effect of IMI and MET in drug-resistant depressed patients.     

Toward a biochemical classification of depressive disorders

Pretreatment urinary MHPG levels were examined in 28 depressed patients as a possible predictor of response to treatment with maprotiline, a tetracyclic antidepressant that exerts potent effects on norepinephrine uptake, but has little effect on serotonin uptake. Maprotiline was administered in doses up to 150 mg/day during the first 2 weeks after which time the dose could be increased incrementally up to 300 mg/day if indicated clinically. At 2 weeks, patients with low pretreatment urinary MHPG levels responded more favorably to treatment than did patients with high MHPG levels. At 4 weeks, patients with low MHPG levels continued to show more favorable responses; however, differences between the two groups were less clear-cut than at 2 weeks. The findings suggest that patients with low pretreatment urinary MHPG levels are more sensitive to, and respond more rapidly to, treatment with maprotiline than patients with high pretreatment urinary MHPG levels.This paper was presented in part at the 132nd Annual Meeting of the American Psychiatric Association in Chicago, Illinois, May 12–18, 1979     

The effect of lithium on urinary MHPG in unipolar and bipolar depressed patients

Twenty-four hour urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression).During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients.There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group.Scholar of the MRC of Canada from the Université de Sherbrooke and subsequently visiting scientist at the NIMH.     

Urinary 3-methoxy-4-hydroxyphenylglycol and the depression-type score as predictors of differential responses to antidepressants.

Pretreatment 24 hr urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the Depression-type (D-type) scores (derived from a multivariate discriminant function equation based on levels of urinary catecholamines and metabolites) were examined as possible predictors of antidepressant responses to either imipramine or alprazolam. In the case of imipramine, the responders had significantly lower pretreatment urinary MHPG levels (p = 0.002) and D-type scores (p less than 0.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p less than 0.05) and D-type scores (p = 0.02) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. For each drug, the effect size for the difference in mean log-transformed D-type scores between responders and nonresponders was greater than the effect size for the difference in mean log-transformed MHPG levels. The difference between the effect sizes was statistically significant for imipramine (p = 0.02) and tended toward significance for alprazolam using two-tailed tests. These results suggest that the D-type equation, which was initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, can also be used to predict differential responses to certain antidepressant drugs in patients with unipolar depressions.     

Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment

This study investigated the effects of antidepressant treatment on platelet activation in depressed patients with ischemic heart disease (IHD). Plasma levels of platelet alpha-granule release products beta-thromboglobulin (BTG) and platelet factor 4 (PF4) were measured in 17 depressed patients with IHD who were treated in a 6-week, double-blind trial with either paroxetine (10 patients) or nortriptyline (7 patients). Baseline measurements of BTG and PF4 were significantly elevated in both drug treatment groups before the initiation of antidepressant therapy compared with those of healthy control subjects. In the paroxetine group, mean PF4 and BTG levels significantly decreased from these elevated baseline values within 1 week of treatment and remained low at 3- and 6-week measurements. In contrast, the nortriptyline group did not exhibit a significant decrease in PF4 or BTG plasma levels after 1, 3, or 6 weeks of treatment. Therefore, platelet activation in depressed patients with IHD seems to be inhibited by the selective serotonin reuptake inhibitor paroxetine. The effect of paroxetine on PF4 and BTG plasma levels suggests that it may reduce platelet aggregation in vivo and may positively impact IHD-related mortality in this population.     

Effects of acute paroxetine treatment on the consumption of cigarette smoking and caffeine in depressed patients

In the present study, we examined the effects of acute treatment with paroxetine on the consumption of cigarette smoking and caffeine in 65 patients who met the DSM-IV criteria for major depressive disorder (M/F: 28/37, age: 48 +/- 15 years). Plasma levels of cotinine or caffeine were analysed using high-performance liquid chromatography (HPLC). The amount of cigarette smoking and plasma levels of cotinine, but not caffeine, decreased 4 weeks after paroxetine treatment. There was no difference between smokers and nonsmokers with respect to their response to paroxetine treatment. In addition, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in responders to paroxetine treatment was higher than those in nonresponders, and there was a negative correlation between the changes in plasma MHPG levels and the changes in Hamilton rating scale for depression (Ham-D) scores before and 4 weeks after paroxetine administration. These results suggest that paroxetine has the potential to reduce the amount of cigarette smoking in depressed smokers, and we reconfirmed our previous results that depressed patients with higher plasma MHPG levels had better response to paroxetine treatment than those with lower plasma MHPG levels using larger depressed samples.     

Pharmacokinetic interaction between imipramine and carbamazepine in patients with major depression

RATIONALE: Despite the fact that carbamazepine (CBZ) is frequently added to the existing tricyclic antidepressant (TCA) therapy, to date little is known about serum levels of pharmacologically active hydroxy metabolites of TCAs, as well as about possible changes in free (non-protein-bound) concentrations of these drugs and their metabolites during such combination treatment of depression. OBJECTIVE: The aim of this study was to evaluate the effect of CBZ on steady-state total and free serum concentrations of imipramine (IMI) and its metabolites, desipramine (DMI), 2-hydroxyimipramine and 2-hydroxydesipramnine, in depressed patients. In addition, the free and total serum concentrations of CBZ and 10,11-epoxycarbamazepine were measured. METHOD: Thirteen patients with DSM-III-R diagnosis of major depression were enrolled in the study. All patients hospitalised at the Department of Psychiatry, Collegium Medicum, Jagiellonian University were treated with IMI at a dose of 2 mg/kg per day for 3 weeks, after which CBZ at a dose of 400 mg/day was added. Steady-state serum concentrations of IMI, CBZ and their metabolites were assayed by HPLC. Free drug concentrations were measured by ultrafiltration. RESULTS: After 2 weeks of combination therapy a significant decrease in mean steady-state total serum concentrations of IMI (from 168.84 +/- 102.18 to 98.12 +/- 43.79 ng/ml) and DMI (from 293.89 +/- 171.93 to 221.85 +/- 153.21 ng/ml) was observed. Simultaneously, steady-state serum concentrations of total hydroxy metabolites and free IMI and its metabolites, measured just before and 2 weeks after CBZ were started, did not differ significantly. In consequence, a significant increase in free fraction of the parent drug was observed (3.36 +/- 3.24% vs 5.75 +/- 3.60%). Also free fraction of DMI tended to be higher after CBZ addition. CONCLUSION: CBZ affects not only the metabolism of IMI and its metabolites, but also their protein binding. Therefore, despite considerable reductions in total serum levels of IMI and DMI, but when the unchanged free fraction concentration of these compounds is maintained, a dosage elevation of IMI does not seem to be necessary after CBZ addition to TCA therapy.     

Effects of carbamazepine on noradrenergic mechanisms in affectively ill patients

Noradrenergic mechanisms have been postulated to account for the anticonvulsant and psychotropic effects of carbamazepine. In order to assess this possibility in man, cerebrospinal fluid (CSF) was obtained from affectively ill patients before and during treatment with carbamazepine (average duration 29 days) at doses averaging 860 mg/day, achieving blood levels of 8.86 g/ml. Neither plasma nor CSF norepinephrine (NE) nor CSF 3-methoxy-4-hydroxyphenylgycol (MHPG) was significantly altered by carbamazepine. Baseline medication-free values in 21 depressed patients were not predictive of the degree of subsequent clinical antidepressant response. CSF NE decreased in four manic patients treated with carbamazepine. The many effects of carbamazepine on noradrenergic mechanisms in animals are discussed in relationship to these first studies of carbamazepine in man.     

Treatment with paroxetine, but not amitriptyline, lowers levels of lipoprotein(a) in patients with major depression

High lipoprotein(a) (Lp(a)) levels constitute a major risk factor for vascular mortality. Major depression also increases the risk of cardiovascular disease. We measured the concentrations of Lp(a) in depressed patients and controls and studied the effects of antidepressant treatment and treatment outcome. Lp(a) levels were analysed at baseline in 35 in-patients with DSM-IV major depression who were then treated in a randomized double-blind manner with amitriptyline (n?=?14) or paroxetine (n?=?21), as well as in 33 healthy controls. Lp(a) levels were re-assessed after 4 weeks of treatment. We found a significant decrease in Lp(a) in patients treated with paroxetine, but not in those treated with amitriptyline. Our results suggest that antidepressant treatment with paroxetine might contribute to a decrease in vascular mortality risk irrespective of treatment outcome.     

Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine

Brain noradrenergic systems have been shown to be altered in opioid dependence and to mediate aspects of opioid withdrawal. Pre-clinical and clinical studies by others have shown that yohimbine, which increases noradrenergic activity, also increases both baseline and fear enhancement of the magnitude of the acoustic startle response (ASR). In a separate report from this experiment, it was shown that yohimbine produced opioid withdrawal-like symptoms, including anxiety, in clinically stable methadone-maintained patients and also produced elevations in the norepinepherine (NE) metabolite, 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol serum levels. The current study reports the effects of intravenous yohimbine hydrochloride, 0.4 mg/kg versus saline (double-blind), on ASR magnitude, plasma MHPG, and cortisol levels in eight methadone-maintained patients and 13 healthy subjects in a double-blind fashion. Yohimbine increased startle magnitude in both groups. There was no basal (placebo day) difference between the startle response of the two groups, but methadone patients had a larger startle magnitude increase in response to yohimbine than healthy controls. Methadone-maintained patients had lower baseline plasma levels of MHPG and similar baseline plasma cortisol levels compared with normal subjects. Yohimbine caused significant elevation in cortisol and MHPG in both groups. Methadone-maintained subjects had higher elevations in cortisol levels and MHPG (methadone main effect) levels in response to yohimbine. However, when MHPG levels were corrected for baseline differences by analysis of covariance (ANCOVA), the yohimbine effect, but not the methadone effect remained statistically significant. These results are consistent with the previous report and support the hypothesis that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and of noradrenergic mechanisms of stress response persist in opioid-agonist maintenance. The ASR effect extends the previous report and provides an additional objective measure for perturbation of noradrenergic and stress responses in these patients.     

Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment.

This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment.     

Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects

The acute and chronic effects of the selective a(2)-antagonist idazoxan were studied in 12 normal volunteers. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), blood pressure and psychological responses to oral challenge doses of idazoxan 40 mg were measured twice, on the first and 22nd day of treatment with idazoxan 40 mg t.d.s. Changes in nocturnal melatonin output were studied on six occasions, before, during and after idazoxan treatment. Although baseline MHPG levels were significantly reduced after chronic treatment with idazoxan, idazoxan challenge did not alter MHPG concentrations on either test day. A small rise in systolic blood pressure occurred after acute but not chronic idazoxan challenge tests. Systolic blood pressure values were significantly lower during the chronic compared with the acute test. Diastolic blood pressure and heart rate were not affected by acute or chronic treatment. Subjects reported increases in self- ratings of arousal and reductions in sedation and anxiety of similar magnitude after acute and chronic idazoxan. Nocturnal plasma melatonin secretion was not altered by drug administration or withdrawal, although urinary 6-sulphatoxymelatonin excretion was significantly reduced on acute withdrawal. The increase in systolic blood pressure and arousal self-ratings after acute idazoxan are in accordance with the reported effects of other a(2)-antagonists, although we did not find increased anxiety or elevated plasma MHPG levels. Chronic idazoxan appears to reduce or normalize activity of noradrenergic systems, indicated by reduced baseline systolic blood pressure and MHPG, and loss of the pressor response to idazoxan. Withdrawal of idazoxan leads to an abrupt fall in noradrenergic activity, as demonstrated by the fall in urinary 6-sulphatoxymelatonin.     

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.     

Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines.Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity).Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels.MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.     

Multiple-dose pharmacokinetics of imipramine and its major active and conjugated metabolites in depressed patients

Imipramine (IMI) and its active metabolites, desipramine (DMI), 2-hydroxyimipramine (2-OH-IMI), and 2-hydroxydesipramine (2-OH-DMI), were assayed by high pressure liquid chromatography in the serum and urine of 14 depressed patients after 1 week of twice-daily treatment with 100 mg of IMI. The concentrations of the glucuronide conjugates of 2-hydroxyimipramine (GA-O-IMI) and 2-hydroxydesipramine (GA-O-DMI) were assessed via enzyme hydrolysis. The range of serum concentrations of IMI and DMI was 65 to 1,064 ng/ml with slight elevation in total active components caused by inclusion of the unconjugated hydroxy metabolites. The average of total active compounds in smokers (239 ng/ml) was less (p less than 0.1) than in nonsmokers (524 ng/ml). The mean serum concentration ratios were 0.24 for 2-OH-IMI/IMI and 0.50 for 2-OH-DMI/DMI ratios, whereas the DMI/IMI ratio was 1.88, indicating more extensive accumulation of DMI. Appreciable glucuronide conjugate accumulation occurred with average serum concentration ratios of 8.13 for GA-O-IMI/2-OH-IMI and 6.22 for GA-O-DMI/2-OH-DMI. Covariance occurred in metabolite/precursor ratios indicating intrapatient similarities in formation/disposition rates of the hydroxy pairs and the conjugate metabolite pairs. Renal clearances of 2-OH-DMI were 35 to 267 ml/min, whereas those of the conjugates were only 10 to 110 ml/min. Total urinary recovery of these metabolites was similar to that reported previously for single IMI doses. The data indicate accumulation of substantial serum concentrations of glucuronide conjugates after therapeutic doses of IMI in depressed patients and similarities within patients in disposition of metabolite pairs.     

The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder

It has been postulated that major depression may be accompanied by significant changes in cell-mediated and humoral immunity related to the pathophysiology or pathogenesis of that illness. We explored the role of 2 cytokines, IL-12 and TGF-beta1, which represent the cytokines of the Th1 and Th3 types, in the pathophysiology of major depressive disorder (MDD). Cytokine levels were measured in 30 major depressed patients at the time of admission and 6 weeks after effective antidepressant treatment; levels were measured once in 30 normal controls. At the time of admission, TGF-beta1 levels of MDD patients showed no differences from normal controls, but IL-12 was significantly higher than in normal controls. However, the IL-12/TGF-beta1 (Th1/Th3) ratios of depressed patients were not different from those of controls. In MDD patients, IL-12 values were significantly decreased after treatment, while TGF-beta1 levels were significantly increased. IL-12/TGF-beta1 ratios of patients were significantly decreased after treatment compared with before treatment. There were no significant correlations between changes in the cytokine levels and changes in scores representing the severity of depression. These findings suggest that major depression is accompanied by immune activation during the acute depressed state, and antidepressant treatments have anti-inflammatory effects.     

The effect of combined treatment with imipramine and amantadine on the behavioral reactivity of central alpha1-adrenergic system in rats

The problem of drug-resistant depression implies a strong need for alternative antidepressant therapies. Recently, it has been shown that joint administration of a tricyclic antidepressant, imipramine (IMI), with amantadine (AMA), a drug already approved for clinical use in the treatment of other diseases, induces a stronger 'antidepressant' effect in the forced swimming test in rats than treatment with either drug given separately. Combined treatment with IMI and AMA also induces up-regulation of dopamine D2 and D3 receptors in the rat brain, and appears to be effective in the treatment of patients with drug-resistant unipolar depression. In the present study, we examined the effect of IMI (5 or 10 mg/kg p.o.) and AMA (10 mg/kg p.o.) given separately or jointly, either as a single dose or repeatedly (twice daily for 14 days) on the development of adaptive changes in the behavioral reactivity of the central alpha1-adrenergic system. Following repeated administration of the higher dose of IMI together with AMA, we observed an increase in clonidine-induced aggression in mice, and significant enhancement of D-amphetamine-induced locomotor hyperactivity, as well as phenylephrine-induced exploratory behavior, in rats. In binding studies using [3H]prazosin, no changes in the density (Bmax) or affinity (Kd) of alpha1-adrenergic receptors were observed in rat brain cortex. However, competition analysis allowed us to observe an increase in the affinity of alpha1-adrenergic receptors (Ki) for an agonist (phenylephrine) upon repeated treatment with IMI, given alone or in combination with AMA. AMA appears to act through several pharmacological mechanisms, none of which has been identified as the chief mode of action. In the light of data obtained in the present study, one can supplement the postulated mechanisms of antidepressant action of AMA by adaptive changes in the reactivity of alpha1-adrenergic receptors, which develop upon repeated combined treatment with IMI.     

Effects of joint administration of imipramine and amantadine in patients with drug-resistant unipolar depression

The paper describes the effect of amantadine (AMA) supplementation on imipramine (IMI) therapy in patients (with treatment-resistant unipolar depression) who fulfilled DSM IV criteria for major depression. Twelve patients were enrolled to the study on the basis of history of their illness and therapy. Following 2 weeks of washout period, the patients were treated with IMI twice daily (100-150 mg/day) for 6 weeks, and then AMA was introduced (twice daily, 100-150 mg/day) and administered jointly with IMI for further 6 weeks. Thereafter, AMA was withdrawn, and the patients were treated with IMI alone for 2 weeks. Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were used to assess efficacy of antidepressant therapy. IMI changed neither HDRS nor BDI score after 3 or 6 weeks of treatment when compared with washout (before treatment). AMA supplementation significantly reduced both HDRS and BDI scores after 3- or 6-week supplementation. AMA augmentation of IMI treatment was beneficial and lasted even after AMA withdrawal. Moreover, pharmacokinetic data indicate that AMA did not influence significantly the plasma concentration of the IMI and its metabolite, desipramine, in the patients during joint treatment with AMA and IMI, what suggests the lack of pharmacokinetic interaction. These results suggest that joint therapy with IMI and AMA may be successful in the treatment-resistant unipolar depression.     

Response to SSRIs and role of the hormonal therapy in post-menopausal depression.

The aim of this study is to prospectively evaluate the antidepressant response to SSRIs in depressed post-menopausal women with or without hormonal therapy (HT), and to analyze the possible influence of basal serum levels of gonadotropins and sexual hormones on the antidepressant response. 170 post-menopausal women with a depressive episode (DSM-IV criteria)--47 on HT and 123 not on HT--started the treatment with an SSRI. Depressive symptoms were assessed at baseline and 7 weeks thereafter by raters blind to treatment regimen. Response rates were 63.2% in the group without HT and 83.7% in the HT group (p=0.013). An inverse correlation emerged between the basal levels of LH and the improvement in HRSD scores (p=0.001) in the group without HT. In conclusion, HT appeared to improve the antidepressant response to SSRIs. Furthermore, in post-menopausal women, LH basal levels may be taken into account as possible predictor of response.     

A double-blind,randomized parallel-group,efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder

S-adenosyl-L-methionine (SAMe) is a natural substance which constitutes the most important methyl donor in transmethylation reactions in the central nervous system. Several clinical trials have shown that SAMe possesses an antidepressant activity. This multicentre study was carried out to confirm both efficacy and safety of SAMe in the treatment of major depression. SAMe was given intramuscularly (i.m.) at a dose of 400 mg/d, double-blind, vs. 150 mg/d oral Imipramine (IMI) in patients with a diagnosis of major depressive episode, with a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >or=18. A total of 146 patients received SAMe whereas 147 received IMI for a period of 4 wk. The two main efficacy measures were endpoint HAMD score and percentage of responders to Clinical Global Impression (CGI) at week 4. Secondary efficacy measures were the final Montgomery-Asberg Depression Rating Scale (MADRS) scores and the response rate intended as a fall in HAMD scores of at least 50% with respect to baseline. The analysis of safety and tolerability was conducted in all treated patients. SAMe and IMI did not differ significantly on any efficacy measure, either main or secondary. Adverse events were significantly less in patients treated with SAMe compared to those treated with IMI. These data show 400 mg/d i.m. SAMe to be comparable to 150 mg/d oral IMI in terms of antidepressive efficacy, but significantly better tolerated. These findings suggest interesting perspectives for the use of SAMe in depression.