Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder

Objective

Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression.

Subjects and methods

Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean ± SD = 39 ± 12) years. Patients were prescribed paroxetine (n = 11) or sertraline (n = 13) for 4 weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4 weeks.

Results

Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group.

Conclusion

Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order.     

Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression

Only two-thirds of depressive patients respond to antidepressant treatment. Recently, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels in refractory depressed patients. Forty-five patients who met the DSM-IV criteria for major depressive disorder (n = 31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twenty-one were male and 24 were female, and their ages ranged from 28 to 71 (mean ± SD = 49 ± 12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4 weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results suggest that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might involve an increase of plasma BDNF levels.     

Lithium addition in antidepressant-resistant depression: effects on platelet 5-HT, plasma 5-HT and plasma 5-HIAA concentration

The efficacy of the addition of lithium to an established course of antidepressant treatment can be explained by a synergistic effect of the two drugs on central 5-HT neurotransmission. In the present study we investigated the effect of lithium addition on the 5-HT concentration in plasma and platelets and the concentration of 5-HIAA. Thirty-nine depressed inpatients who fulfilled the DSM-IV criteria for major depressive disorder and who did not respond to monotherapy with either imipramine or fluvoxamine participated in this study. Concentration of 5-HT in both plasma and platelets did not change significantly during lithium addition. The 5-HT ratio (plasma concentration/platelet concentration) shows a small non-significant increase after 3 weeks lithium addition. The mean concentration of 5-HIAA shows a significant increase during lithium addition; with no difference between the imipramine and the fluvoxamine sample. The increments in 5-HIAA concentration during lithium addition are indicative of an increased 5-HT turnover.     

Platelet serotonin concentration and suicidal behavior in combat related posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a serious and global problem, a psychiatric disorder that frequently occurs with different comorbidities, and is associated with a high suicide rate. Pathophysiologically, both PTSD and suicidal behavior are related to disturbances in the central serotonergic system. Serotonin (5-hydroxytryptamine, 5-HT) controls emotional behavior, anxiety, impulsivity and aggression, and nearly all known antidepressants and antianxiety drugs affect 5-HT transmission. Platelet 5-HT can be used as a limited peripheral marker of the central serotonergic synaptosomes, since it is related to particular basic psychopathological characteristics of several psychiatric disorders. Platelet 5-HT concentration has been reported to be similar in PTSD subjects and healthy controls, but suicidal patients across different psychiatric diagnoses have reduced platelet 5-HT concentration. This study examined platelet 5-HT concentration by the spectrofluorimetric method in male subjects: 73 suicidal and 47 non-suicidal veterans with current and chronic combat related PTSD, 45 suicidal and 30 non-suicidal comparative non-PTSD subjects and 147 healthy men. The presence of suicidal behavior (score=0, non-suicidal; scores > or =1, suicidal) was assessed with the Hamilton Depression Rating Scale-17 (HDRS). Platelet 5-HT concentration was significantly lower in suicidal PTSD and non-PTSD patients compared to non-suicidal patients or healthy controls. Since the majority of patients scored very low on item 3 of HDRS, no significant correlation between suicidal scores and platelet 5-HT concentration was found. These results show that reduced platelet 5-HT concentration is related to suicidal behavior in PTSD, and suggest that platelet 5-HT concentration might be used as a peripheral marker to predict suicidal behavior across psychiatric diagnoses.     

The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease

OBJECTIVES: The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. MATERIALS AND METHODS: A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. RESULTS: No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). CONCLUSION: The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.     

Psychological traits and platelet monoamine oxidase activity in eating disorder patients: their relationship and stability

Self-reported behavior and attitudes towards eating [Eating Disorder Inventory-2; Garner DM (1991). Eating Disorder Inventory-2: Professional Manual. Odessa, Fl.: Psychological Assessment Resources; Estonian version Podar I, Hannus A, Allik J (1999). Personality and Affectivity Characteristics Associated With Eating Disorders: a Comparison of Eating Disordered, Weight-Preoccupied, and Normal Samples. J Pers Assess; 73(1), 133-147] and the activity of platelet monoamine oxidase (MAO) was studied in 11 patients with anorexia nervosa (AN), 43 patients with bulimia nervosa (BN) and a healthy control group (n=138). Nineteen patients filled in the EDI-2 questionnaire and donated blood samples three times with three month intervals in order to determine platelet MAO activity. Eating disordered (ED) patients scored higher on all EDI-2 subscales and had lower MAO activity compared to the control group. They also scored higher than the control group on the Neuroticism domain but lower on the Extraversion, Openness, and Conscientiousness domains of the NEO-PI-R questionnaire. The average stability of MAO on different occasions (r=.56) was slightly smaller than the stability of the EDI-2 scores (r=.70). The lack of correlations between personality dispositions and MAO activity indicates that they have independent influence on eating disorders. A possible relationship between neurochemical mechanisms and psychological symptoms of eating disordered behavior is discussed.     

Sertraline treatment of patients with major depressive disorder who failed initial treatment with paroxetine or fluvoxamine

This study was undertaken to examine the long-term effectiveness and safety of switching to sertraline from other selective serotonin reuptake inhibitors (SSRIs) in the treatment of non-remitted or treatment-intolerant major depressive disorder. The study included 25 patients with major depressive disorder according to DSM-IV-TR criteria. None had achieved remission with paroxetine or fluvoxamine, but each had been used in an adequate dose for an adequate time period or had been intolerant of these SSRIs. Most patients (n=22, 88%) were non-remitters. Switching was accomplished by gradual cross-titration and tapering. We conducted assessments at baseline and at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. Outcomes were assessed using the Quick Inventory of Depressive Symptomatology-Self-Report, Japanese version (QIDS-SRJ) score (primary outcome), the 17-item Hamilton Depression Rating Scale (HDRS), and the Clinical Global Impressions (CGI) scale. Mean QIDS-SRJ and HDRS scores improved significantly from baseline to week 8 and week 24. At the respective endpoints of weeks 8 and 24, remitters on QIDS-SRJ (≤5) were 2 of 25 (8%) and 4 of 25 (16%). At weeks 8 and 24, 11 of 25 (44%) were responders on QIDS-SRJ (≥50% reduction). Five patients (20%) terminated early, before week 8, because of side effects and/or lack of efficacy. These preliminary data suggest that the switching strategy from paroxetine or fluvoxamine to sertraline might be effective and well-tolerated in patients with non-remitted or treatment-intolerant major depressive disorder.     

Fluoxetine versus sertraline in the treatment of patients with undifferentiated somatoform disorder: a randomized, open-label, 12-week, parallel-group trial

The present study was conducted to compare the effectiveness and tolerability of fluoxetine and sertraline in the treatment of undifferentiated somatoform disorder (USD), using the Patient Health Questionnaire (PHQ-15), which was specifically designed for assessing the severity of somatic symptoms. A randomized, 12-week, open-label trial of fluoxetine (10-60 mg/d) and sertraline (25-350 mg/d) in patients with USD was conducted. Six visits, at baseline and weeks 1, 2, 4, 8, and 12, were scheduled. Assessments for effectiveness and tolerability were conducted at each visit. The primary effectiveness measure was the mean change in PHQ-15 total score, from baseline to the end of treatment. Secondary effectiveness measures were the mean changes in total scores on the Beck Depression Inventory (BDI) and the 12-item General Health Questionnaire (GHQ-12), from baseline to the end of treatment. A total of 45 subjects were enrolled; of them, 28 were randomly assigned to receive fluoxetine and 17 to receive sertraline. The total score on the PHQ-15 from baseline to the end of treatment significantly decreased in the fluoxetine (-10.7, p<0.0001) and sertraline (-10.3, p<0.0001) treatment groups, with no between-group difference (F=0.0701, p=0.7924). Overall, both treatments were well tolerated and no serious adverse event was reported. This study suggests that both agents may have a potential role in the treatment of USD. A double-blind, placebo-controlled trial and/or head-to-head comparison study with larger samples are required to draw more definite conclusions.     

Alterations in hypothalamic-pituitary-adrenal/thyroid (HPA/HPT) axes correlated with the clinical manifestations of depression

The alterations of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are important neuroendocrine abnormalities in depression. We aimed to identify some potential associations between these alterations and the clinical manifestations of depression in a sample of Chinese origin. 565 depressed patients of Chinese Han region were collected and seven kinds of hormones in HPA and HPT axes were detected. A 17-item Hamilton Depression Rating Scale (HAMD-17) and a 14-item Hamilton Anxiety Rating Scale (HAMA-14) were used to evaluate the baseline condition of each patient. 519 patients were enrolled into analysis. The patients with dysfunction of HPA axis had susceptibility to agitation symptoms (HAMD9 item) and cognitive disorders (HAMD2, 3 and 9 items), while those with normal function of HPA axis had susceptibility to shallow sleep (HAMD5 item). The patients with dysfunction of HPT axis had susceptibility to difficulty in falling asleep (HAMD4 item), weight loss (HAMD16 item) and gastrointestinal symptoms (HAMD12 item). Besides, the patients with dysfunctions of both HPA and HPT axes showed remarkable retardation symptoms (HAMD8 item). These findings might provide some evidences for the clinical subgrouping and management individualization of depressed patients according to the neuroendocrine alterations.     

The impact of ziprasidone in combination with sertraline on visually-evoked event-related potentials in depressed patients with psychotic features

BACKGROUND: The use of atypical antipsychotics in major depression complicated by psychotic features has not been extensively investigated. Event-related potentials (ERP) have been reported to be impaired in depressed patients, probably due to serotonergic hypofunction. The objective of this study was to examine the effects of a combination therapy with ziprasidone and sertraline on ERP in major depression with psychotic features. METHODS: 19 patients with major depression with psychotic features were treated with ziprasidone and sertraline. Before and after four weeks of treatment, visually-evoked ERP (P3 -- oddball paradigm) were investigated. RESULTS: While a significant clinical improvement assessed with the Brief Psychiatric Rating Scale and Hamilton Depression Rating Scale was noted, no significant changes in weight, basal prolactin values and scores on the Extrapyramidal Symptoms Scale were observed. A significant prolongation (p = 0.041) of the QTc-interval between baseline and endpoint showed no clinical symptoms. Combination treatment with ziprasidone and sertraline over 4 weeks was associated with a significant decrease (p = 0.033) of P3 latencies from baseline to week 4. After a four week treatment, significantly (p = 0.008) fewer patients showed pathologically P3 latencies (>450 ms) than at baseline. DISCUSSION: Our data, showing that ziprasidone in combination with sertraline lead to a decrease of prolonged P3 latencies, are in line with previous studies showing a decrease of prolonged P3 latencies by antidepressant treatment.     

A monoamine oxidase B gene variant and short-term antidepressant treatment response

Genetic differences among patients suffering from Major Depression are likely to contribute to interindividual differences in medication treatment response. Thus, the identification of gene variants affecting drug response is needed in order to be able to predict response to psychopharmacological drugs. This study analyzed a possible association of the common A644G single nucleotide polymorphism (SNP) within intron 13 of the monoamine oxidase B (MAOB) gene with antidepressant treatment response. The study population consisted of n = 102 patients with major depression (criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; DSM-IV) participating in a randomized double-blind controlled clinical trial, conducted at 50 centers in Germany, comparing the efficacy of mirtazapine and paroxetine during 6 weeks of treatment. Overall, female patients homozygous for the A-allele had a significantly faster and more pronounced antidepressant treatment response than AG/GG-carriers. In paroxetine-treated females these differences remained statistically significant. In mirtazapine-treated females homozygous for the A-allele compared to AG/GG-carriers, HAMD-17 scores during the study period were constantly and markedly lower, but not statistically different. In males, we found no association between the MAOB A644G intron 13 SNP and antidepressant treatment response. Our data provide first suggestive evidence that the MAOB A644G SNP is involved in the outcome of treatment with mirtazapine or paroxetine in females with major depression. To confirm the role of the MAOB A644G gene variant in antidepressant treatment response, independent replications are needed. If replicated, the MAOB A644G polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.     

Psychomotor retardation in depression: biological underpinnings, measurement, and treatment

Psychomotor retardation is a long established component of depression that can have significant clinical and therapeutic implications for treatment. Due to its negative impact on overall function in depressed patients, we review its biological correlates, optimal methods of measurement, and relevance in the context of therapeutic interventions. The aim of the paper is to provide a synthesis of the literature on psychomotor retardation in depression with the goal of enhanced awareness for clinicians and researchers. Increased knowledge and understanding of psychomotor retardation in major depressive disorder may lead to further research and better informed diagnosis in regards to psychomotor retardation. Manifestations of psychomotor retardation include slowed speech, decreased movement, and impaired cognitive function. It is common in patients with melancholic depression and those with psychotic features. Biological correlates may include abnormalities in the basal ganglia and dopaminergic pathways. Neurophysiologic tools such as neuroimaging and transcranial magnetic stimulation may play a role in the study of this symptom in the future. At present, there are three objective scales to evaluate psychomotor retardation severity. Studies examining the impact of psychomotor retardation on clinical outcome have found differential results. However, available evidence suggests that depressed patients with psychomotor retardation may respond well to electroconvulsive therapy (ECT). Current literature regarding antidepressants is inconclusive, though tricyclic antidepressants may be considered for treatment of patients with psychomotor retardation. Future work examining this objective aspect of major depressive disorder (MDD) is essential. This could further elucidate the biological underpinnings of depression and optimize its treatment.     

The potential antidepressant-like effect of imidazoline I2 ligand 2-BFI in mice

The compound 2-(2-benzofuranyl)-2-imidazoline (2-BFI) is a 2-imidazoline derivative that selectively inhibits the in vitro activity of monoamine oxidase-A and it is also an imidazoline I(2) agonist. However, the antidepressant potential of this compound and its mechanism of action have not been well defined. Therefore, in this study we investigated the antidepressant-like effect of 2-BFI in mice. 2-BFI (100 and 300μmol/kg, s.c.) significantly reduced the immobility time on the tail suspension test (TST) without changing locomotion in the open field test. The reduced the immobility time of 2-BFI (100μmol/kg, s.c.) was confirmed with the forced swimming test (FST). The antidepressant-like effect of 2-BFI (100μmol/kg, s.c.) in the TST was prevented by pretreatment with idazoxan (0.4μmol/kg, i.p., a I(2) site antagonist), methysergide (4μmol/kg, i.p., a non-selective serotonergic receptor antagonist) and haloperidol (0.1μmol/kg, i.p., a non-selective dopaminergic receptor antagonist). The anxiolytic effect of 2-BFI was also evaluated, using the elevated plus-maze test. 2-BFI (300μmol/kg, s.c.) was able to significantly increase the % of number of entries and the % of time spent in the open arms, indicating that it possesses an anxiolytic effect at high doses. In conclusion, these results suggest that the antidepressant-like effect of 2-BFI might involve serotonergic, dopaminergic and imidazoline systems, and then the imidazoline site could represent a new pharmacological target for the treatment of depression.     

Evidence for the involvement of the monoaminergic system in the antidepressant-like effect of magnesium

Literature data has shown that acute administration of magnesium reduces immobility time in the mouse forced swimming test (FST), which suggests potential antidepressant activity in humans. However, its mechanism of action is not completely understood. Thus, this study is aimed at investigating the antidepressant-like action of magnesium and the possible involvement of the monoaminergic system in its effect in the FST. The immobility time in the FST was significantly reduced by magnesium chloride administration (30–100 mg/kg, i.p.) without accompanying changes in ambulation when assessed in an open-field test. The pre-treatment of mice with NAN-190 (0.5 mg/kg, i.p. a 5-HT_1A receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist), ritanserin (4 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), ketanserin (5 mg/kg, a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), haloperidol (0.2 mg/kg, i.p., a non selective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) 30 min before the administration of magnesium chloride (30 mg/kg, i.p.) significantly prevented its anti-immobility effect in the FST. Moreover, the administration of sub-effective doses of fluoxetine (10 mg/kg, i.p., serotonin reuptake inhibitor), imipramine (5 mg/kg, i.p., a mixed serotonergic noradrenergic reuptake inhibitor), bupropion (1 mg/kg, i.p., dopamine reuptake inhibitor) was able to potentiate the action of sub-effective doses of magnesium chloride. In conclusion, the present study provides evidence indicating that the antidepressant-like effect of magnesium in the FST is dependent on its interaction with the serotonergic (5-HT_1A and 5-HT_2A/2C receptors), noradrenergic (α₁- and α₂- receptors) and dopaminergic (dopamine D₁ and D₂ receptors) systems.     

Therapeutic effects of the selective serotonin noradrenaline reuptake inhibitor milnacipran on depressive symptoms in patients with Alzheimer's disease

To clarify the profile of depressive symptoms in major depressive episodes in patients with Alzheimer's disease (AD-MD), we compared AD-MD with major depressive disorder in non-demented elderly patients (MDD) matched for age, using the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇). In addition, to clarify which depressive symptoms of AD patients respond to treatment with the selective serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran, we compared the HAM-D₁₇ average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score, and GAF score according to the DSM-IV evaluation of AD-MD patients at baseline and at the endpoint (12 weeks).     

Antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: Evidence for the involvement of the monoaminergic system

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10–300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression.     

Antidepressant-like effect of the extract of Rosmarinus officinalis in mice: Involvement of the monoaminergic system

Rosemary, Rosmarinus officinalis L. (Labiatae) has several therapeutic applications in folk medicine in curing or managing a wide range of diseases, including depression. In this study, the effect of the hydroalcoholic extract of the stems and leaves of this plant was investigated in two behavioral models, the forced swimming test (FST) and tail suspension test (TST) in mice. The extract of R. officinalis produced an antidepressant-like effect, since the acute treatment of mice with the extract by p.o. route significantly reduced the immobility time in the FST (100 mg/kg) and TST (10–100 mg/kg), as compared to a control group, without accompanying changes in ambulation in the open-field test. Moreover, the repeated administration (14 days) of the hydroalcoholic extract of R. officinalis by p.o. route also produced an antidepressant-like effect in the TST (100–300 mg/kg). The pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT_1A receptor antagonist), ketanserin (5 mg/kg, i.p., a 5-HT_2A receptor antagonist), 1-(m-chlorophenyl) biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT₃ receptor agonist), prazosin (1 mg/kg, i.p., an α_1-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), but not yohimbine (1 mg/kg, i.p., an α_2-adrenoceptor antagonist) was able to reverse the anti-immobility effect of the extract (10 mg/kg, p.o.) in the TST. The combination of MDL72222, (0.1 mg/kg, i.p., a 5-HT₃ receptor antagonist) with a sub-effective dose of the extract of R. officinalis (1 mg/kg, p.o.) produced an anti-immobility effect in the TST. The results suggest that the antidepressant action of the extract of R. officinalis is mediated by an interaction with the monoaminergic system and that this plant should be further investigated as an alternative therapeutic approach for the treatment of depression.     

Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5–5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT₃ receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na⁺ K⁺ ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT_2A/2C and 5-HT₃ receptors).     

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in major depressive disorder patients

Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary α-amylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in MDD patients. The present study measured sAA and salivary cortisol levels in patients with MDD. The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 88 patients with MDD and 41 healthy volunteers following the application of electrical stimulation stress. Patients with major depressive disorder were 8 points or more on Hamilton Depression Scale (HAM-D) scores. Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores in patients with major depressive disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with MDD were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between MDD patients and healthy controls. The threshold of electrical stimulation applied in MDD patients was lower than that in healthy controls. SAA levels in female MDD patients were significantly elevated relative to controls both before and after electrical stimulation. Finally, there were no differences in salivary cortisol levels between major depressive patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness of novel and uncontrollable situations in patients with MDD. These preliminary results suggest that sAA might be a useful biological marker of MDD.     

Autonomic modulation in healthy first-degree relatives of patients with major depressive disorder

Background

Cardiac mortality is known to be increased in patients with major depression. Several studies have reported an imbalance within the autonomic nervous system (ANS) of patients with major depressive disorder (MDD) as one putative cause. Since a heritability of autonomic modulation was demonstrated in healthy subjects, we aimed to investigate autonomic modulation in first-degree relatives of patients with MDD to find potential autonomic imbalances.

Methods

We included 30 patients with MDD, 30 of their first-degree relatives (siblings or offspring) and 30 matched healthy controls in our study. We obtained a high resolution electrocardiogram and beat to beat blood pressure measurements for 30 min at rest. Linear and nonlinear parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS) were calculated.

Results

Parameters of HRV and BRS did not differ significantly between relatives and controls. We found significant differences between patients and controls for some HRV and BRS parameters confirming results of previous studies.

Discussion

Findings of our study suggest that an imbalance of autonomic function is related to patients with depression and not to first-degree relatives. Thus, a genetic background for autonomic dysfunction is rather unlikely.