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To investigate the effects of dietary fiber on follicular atresia in pigs fed a high-fat diet, we fed 32 prepubescent gilts a basal diet (CON) or a CON diet supplemented with 300 g/d dietary fiber (fiber), 240 g/d soy oil (SO), or both (fiber + SO). At the 19th day of the 4th estrus cycle, gilts fed the SO diet showed 112% more atretic follicles and greater expression of the apoptotic markers, Bax and Caspase-3, and these effects were reversed by the fiber diet. The abundance of short-chain fatty acid-producing microbes was decreased by the SO diet, but this effect was reversed by fiber treatment. Concentrations of serotonin and melatonin in the serum and follicular fluid were increased by the fiber diet. Overall, dietary fiber protected against high-fat feeding induced follicular atresia at least partly via gut microbiota-related serotonin–melatonin synthesis. These results provide insight into preventing negative effects on fertility in humans consuming a high-energy diet.
Reward sensitivity is an increasingly used construct in psychiatry, yet its possible inner structure and relationship with other affective variables are not well known.
A reward sensitivity measurement scale was constructed on the basis of large item pool collected from birth cohort representative samples (the Estonian Children Personality Behaviour and Health Study; original n = 1238). Affective Neuroscience Personality Scale (ANPS) and the Adult Attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS) were administered in young adulthood. A variant (rs4570625) of the gene encoding tryptophan hydroxylase 2 (TPH2) that is responsible for the synthesis of central serotonin was genotyped.
Reward sensitivity consisted of two orthogonal components, operationally defined as Openness to Rewards and Insatiability by Reward, that respectively characterise the striving towards multiple rewards and the strong pursuit and fixation to a particular reward. While SEEKING and PLAY (and to lower extent CARE) of the ANPS co-varied with Openness to Rewards, FEAR, SADNESS, and ANGER were related to Insatiability by Reward. The total score of ASRS was moderately correlated with Insatiability by Reward, while the association with Openness to Rewards was negligible. However, ASRS Inattention had some negative relationship with the Social Experience facet of Openness to Rewards. The T/T homozygotes for the TPH2 promoter polymorphism had lower Insatiability by Reward but not Openness to Rewards.
Behaviours sensitive to rewards are separable to the components of variability and fixation, and these components are differentially related to affective aspects of personality, attention, and hyperactivity as well as to TPH2 genotype.
Serotonin syndrome is a potentially deadly reaction that occurs as a result of: therapeutic use of medicament, as a consequence of drugs’ interaction or intentional overdosing with medicaments that influence on the serotonin metabolism.
In this paper the authors presented brief theoretical consideration of etiological causes for clinical onset of serotonin syndrome, clinical features of serotonin syndrome and difficulties in discovering the same in clinical practice. Furthermore, diagnostic criteria, differential diagnoses, treatment and prevention of serotonin syndrome were presented.
Authors presented the case report of female inpatient treated in Psychiatry Clinic in Tuzla University Clinical Centre, whose state of somatic deterioration understood originally within the clinical features of basic diseases. Correspondingly, the dose of pro-serotoninergic antidepressant was increased. Subsequently, and timely recognition of serotonin syndrome, and therapeutic corrections of medication, were of great importance in the course of patients’ recovery.
Gene variants of the serotonin transporter have been associated with vulnerability to affective disorders. In particular, the presence of one or two copies of the short (s) allele of the 5-HTTLPR polymorphism has been associated with reduced serotonin transporter expression and function, and vulnerability to affective disorders. To test for an association between variants of the serotonin transporter gene polymorphism (5-HTTLPR) and relevant clinical features of borderline personality disorder (BPD), a psychiatric disorder with symptoms characteristic for serotonin dysfunction, 77 women with BPD were genotyped in the 5-HTTLPR polymorphism. They rated their subjective experience of borderline-specific, depressive, anxious and obsessive-compulsive symptoms, and were interviewed about lifetime incidence of suicide attempts and self-harming acts. Carriers of two s alleles of the 5-HTTLPR reported more symptoms of borderline, depression, anxiety and obsessive-compulsive behaviours, but not of suicidal and self-injury behaviour, compared to carriers of a long (l) allele. This indicates that the 5-HTTLPR ss homozygous genotype might influence serotonin function affecting susceptibility to both borderline-specific, depressive, anxious and obsessive-compulsive symptoms in BPD, and leading to a more severe symptomatology related to these clinical features. Further, this suggests that 5-HTT gene variants may not be as influential on suicidal and self-injury behaviour in BPD.
Recent studies by Cloninger suggest that the temperament dimension of harm avoidance might be related to serotonergic activity. Since serotonergic mechanisms equally play a major role in sleep regulation, we decided to use Cloninger’s psychobiological model of temperament and character to assess whether there is a link between psychophysiologic insomnia and specific personality traits. Chronic insomnia is a common complaint in modern society, and it is still controversial whether insomniacs share specific personality traits. Thirty-two chronic insomniacs (<50 years) were studied. They underwent polysomnography for two consecutive nights and filled out the 226-item self-questionnaire of Temperament and Character Inventory as well as the Hospital Anxiety and Depression scale. (1) Harm avoidance for all subscores was significantly higher in insomniac patients when compared with controls; (2) self-directedness scores were lower in insomniacs; (3) sleep latency was positively correlated to harm avoidance; (4) HA1 (anticipatory worry) was negatively correlated to REM latency. Temperament and Character Inventory is a useful tool in the investigation of chronic insomnia. Serotonergic mechanisms might explain the high incidence of harm avoidance as personality trait in psychophysiologic insomniac patients. Further studies are needed to see whether harm avoidance could be a psychological vulnerability marker for primary insomnia and be used as predictor of SSRI treatment responders.
Chronically stressed adult male Balb C mice were submitted to the tail suspension test. Chronic immobilization stress (6 h/d for 14 consecutive days) induced a significant reduction in immobility time when compared to non-stressed controls. Pretreatment with LY 53857, a serotonin 5HT2 antagonist, and IPS 339, a selective beta-2 adrenoceptor blocker, reversed immobility time to the levels of non-stressed controls. Chronic administration of corticosterone (100 mg/kg for 7 d) did not modify immobility time as compared to saline treated controls. It is suggested that both serotonergic and adrenergic pathways in the brain may participate in the stress-induced changes occurring in the tail suspension test response and that corticosterone does not appear to play a role in this process.
Atypical neuroleptics that block serotonin 2A (5-HT 2A) and dopamine 2 (D2) receptors have been shown to possess efficacious antipsychotic activity. We assessed the efficacy of the addition of the 5-HT 2A/2C and α2 antagonist mianserin to ongoing haloperidol treatment in chronically hospitalized (> 10 years) drug-resistant schizophrenic patients (N = 12). The patients were assessed at baseline and every three months for one year with the Brief Psychiatric Rating Scale and the Clinical Global Impression. Results showed a significant (but < 10%) improvement in the core symptoms of schizophrenia; however, only the reduction (by 43%) in anxiety was clinically relevant (P < 0.0001). The beneficial effect of mianserin may be related to the combined blockade of 5-HT 2A and histamine (H1) receptors.
The purpose of this chronoepidemiologic study was to investigate the time-relationships between the yearly variations in occurrence of violent suicide in Belgium and the yearly variations in various biochemical, metabolic and immune variables in the Belgian population. The weekly mean number of deaths due to violent suicide for all of Belgium for the period 1979–1987 was computed. Twenty-six normal volunteers had monthly blood samplings during one calendar year for assays of plasma L-tryptophan (L-TRP), competing amino acids (CAA), and melatonin levels, maximal [3H]paroxetine binding to platelets, serum total cholesterol, calcium, magnesium, and soluble interleukin-2 receptor concentrations, and number of CD4+ T, CD8+ T and CD20+ B lymphocytes. The annual rhythm in violent suicide rate is highly significantly synchronized with the annual rhythms in L-TRP, [3H]paroxetine binding, cholesterol, calcium, magnesium, CD20+ B cells, and CD4+/CD8+ ratio; the mean peak (violent suicide, [3H]paroxetine binding) or nadir (all other variables) occurs around 3 May. There were significant inverse time-relationships between the time series of violent suicide rate and L-TRP, L-TRP/CAA ratio, total cholesterol, calcium and magnesium, CD4+/CD8+ T cell ratio and number of CD20+ B cells. Maximal [3H]paroxetine binding to platelets was significantly and positively related to the time series of violent suicide. An important part (56.4%) of the variance in mean weekly number of violent suicide rate was explained by the time series of L-TRP, cholesterol and melatonin.
It has been suggested that low serum cholesterol interferes with brain serotonergic functioning, which results in increased suicidal and aggressive tendencies. To test this hypothesis we investigated the relationship between serum cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride levels, and serotonin uptake by blood platelets in 17 healthy men aged 39.5 ± 10.2 years. Platelet serotonin uptake and serum lipids were assayed concomitantly for each individual. Serum cholesterol levels and other serum lipid levels did not correlate with serotonin uptake by platelets at the concentration of 2 × 10−5 M (a concentration within the maximal uptake capacity range). The results indicate no influence of cholesterol on serotonin uptake, as opposed to some investigators who suggested that high risk of suicide and aggressiveness in hypocholesterolemic individuals is related to impaired serotonin transport.
Platelet serotonin-binding (Bmax), using tritiated-seroionin as the ligand, was determined in 75 patients suffering from major depression with melancholia and in 26 patients diagnosed from dysthymic disorder. Twenty-five normal subjects were used as a control group. The melancholic group had significantly lower Bmax values (mean: 6.7 ± 6.1 pmol/108 platelets) than either dysthymic (9.3 ± 3.9 pmol/108 platelets) or control (9.2 ± 4.8 pmol/108 platelets) groups, while there were no significant differences between the two latter groups. There was also a significant difference on postdexamethasone Cortisol between melancholic (6.3 ± 7.1 μg/dL) and dysthymic (1.4 ± 1.4 μg/dL) groups, with a higher rate of nonsuppressors in melancholic groups. Although both tests were abnormal in the melancholic group, no relationship was found between platelet serotonin-binding and the dexaniethasone suppression test.
Venlafaxine is a serotonin-noradrenaline reuptake inhibitor (SNRI) that has no affinity for muscarinic, adrenergic or histaminergic receptors. In short-term trials, the adverse effects that occurred more often with venlafaxine than with placebo included nausea, somnolence, dizziness, dry mouth, and sweating. Rapid titration of the dose of venlafaxine to higher levels appeared, not unexpectedly, to be associated with an increased incidence of side effects. Side effects that appeared to be dose related included insomnia, nausea and sexual dysfunction. The incidence of nausea and dizziness was highest during the first 2 or 3 weeks of therapy and decreased rapidly thereafter. Somnolence also decreased over time. At high doses blood pressure increases were reported in a small percent of patients on venlafaxine and antidepressant drugs but were uncommon at the venlafaxine dose of 75–150 mg daily. Studies with venlafaxine in healthy volunteers indicate a low potential for drug-drug interactions. Overdoses have been reported in 14 of 3,082 patients administered venlafaxine in clinical trials, and no deaths were reported among these patients. Overdoses of venlafaxine induced mainly drowsiness and lethargy.
Alcohol withdrawal is a clinically and etiologically heterogeneous syndrome caused by a complex interaction of environmental (e.g., amount of ethanol) and genetic factors. Multiple genes are considered to be involved in various components of the syndrome, each of them contributing only modestly to withdrawal vulnerability. Association studies using candidate genes of the dopamine, serotonin, gabaergic and opioidergic systems are reviewed and methodological limitations are discussed.
Abnormalities in the serotonergic system have been implicated in the pathophysiology of depressive disorders. Human platelets possess serotonin-2A (5-HT2A) receptors, and previous research using LSD or ketanserin as ligands have indicated that their number is increased in depressed patients. Compared to other ligands previously used in platelet studies, DOI is highly selective for the 5-HT2A receptor and binds to its high-affinity state, therefore labeling only the receptors that are biologically coupled to the G-protein. We determined the density (Bmax) and the affinity (Kd) of 5-HT2A receptors labeled by [125I]-DOI in platelets from 21 untreated patients with major depression and 21 healthy volunteers. The density of the 5-HT2A binding sites was found to be increased in platelets from female depressed patients as compared to controls. No changes were observed in the Kd. We did not find any relationship between the binding parameters and either the severity of the depressive episode or the suicidal tendencies of the patients. Our results show that the number of coupled platelet 5-HT2A receptors is increased in depressed patients, indicating that platelet 5-HT2A receptor function is enhanced in depression.
In 32 patients with panic disorder with or without agoraphobia, Bmax measures of 5-HT binding in platelets did not differ from normal controls at baseline. Plasmatic cortisol levels were significantly higher than controls in the morning and in the evening measures as well as in post-dexamethasone assays. Following an 8-week treatment period with alprazolam plus behavioral guidance encouraging exposure, Bmax values did not alter but cortisol measures diminished significantly. Measures of phobic avoidance were negatively correlated with 5-HT Bmax values. Plasmatic cortisol correlated positively with the number of situational panic attacks in the month before treatment. There were no correlations between cortisol and 5-HT Bmax measures. A possible link between serotonin function and phobic avoidance is discussed. Cortisol changes were interpreted as being related to the global severity of the anxious state.
The A allele of the 5-HT2A gene (–1438A/G polymorphism) has been associated with anorexia nervosa in four studies, but not in three others. One possibility to explain such a discrepancy is that the A allele acts as a modifying rather than a vulnerability allele. To test this hypothesis, we increased our initial sample of 102 trios [Mol. Psychiatry 7 (2002) 90] with 43 new patients with anorexia nervosa and 98 healthy controls. In addition to confirming the absence of association on the global sample of 145 patients, we found that patients with the A allele had a significantly later age at onset of the disease (P = 0.032). Furthermore, the A allele was also transmitted with an older age at onset (P = 0.023) using a quantitative-trait TDT approach. The A allele may thus act as a modifying factor (delaying onset), potentially explaining variations of allele frequency across samples, in which differences in average age at onset are not only possible, but also expected. Taking into account vulnerability genes, but also genes modifying the expression of the disorder, will help to disentangle the complexity of the etiological factors involved in anorexia nervosa.
We report three cases in which toxic serotonin syndrome developed in relation to three different selective serotonin reuptake inhibitors (SSRI) (ie, fluoxetine, sertraline, paroxetine), and which all responded to the discontinuation of the SSRI and also to an additional propranolol treatment.
Panic disorder is a chronic condition for many patients and can be socially, emotionally and occupationally disabling. Until recently, clomipramine and alprazolam were the only drugs approved for its treatment. While widely used in the US and Europe, both belong to drug classes (tricyclics and benzodiazepines) with well-recognised side effects that can be problematic and thus limit their use. Recently, paroxetine became the first selective serotonin reuptake inhibitor to receive approval and licensing for panic disorder.
The short- and long-term efficacy and tolerability of paroxetine in panic disorder has been established in clinical trials of almost 1,000 patients meeting Diagnostic and Statistical Manual (DSM)-IIIR criteria for panic disorder, with or without agoraphobia. In a 12-week double-blind study of 120 panic patients receiving standardised cognitive therapy, paroxetine was significantly more effective than placebo in reducing panic attack frequency. In a 12-week placebo-controlled comparison in 367 panic patients, paroxetine was at least as effective as clomipramine and better tolerated. There was also some evidence that paroxetine had an earlier onset of action than clomipramine.
A 9-month extension of the placebo-controlled comparison with clomipramine showed that the efficacy of paroxetine and clomipramine is maintained when treatment is continued into the longer term. In a relapse prevention study, 105 responders to 3 months' treatment with paroxetine or placebo were re-randomised, either to continue existing treatment or to receive placebo for 3 months. Only 5% of patients who continued to take paroxetine experienced a relapse compared with 30% of those who switched to placebo (P = 0.002). Paroxetine was generally well tolerated. In the short-term trials, the frequency of withdrawals due to adverse events (7.3%) was lower than that for placebo (11.4%) or clomipramine (14.9%). In the longer term, the dropout rate due to adverse events increased in the clomipramine group (19.0%) but was unchanged in the paroxetine group (7.4%). Since most patients with panic disorder will require prolonged treatment, the long-term tolerability of paroxetine and its lack of potential for dependence are important advantages that will encourage good compliance with treatment and improve the quality of life of patients.
This study tested suicidality in relation to cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and the dexamethasone suppression test. Patients with nonsuppression of cortisol had the highest scores of the Suicide Assessment Scale (SUAS) and the Montgomery Asberg Depression Rating Scale (MADRS), respectively (P < 0.05; P < 0.01). The results persisted when analysed for covariance with CSF-5-HIAA. We have previously noted an elevated suicide risk in suicide attempters with high SUAS-scores, why a large part of nonsuppressors may be at high risk for future suicide.
The identification of the brain structures and neurotransmitters responsible for the generation and/or modulation of P300 could lead to important clinical implications. Since serotonin disturbances seem to play a critical role in depression, the aim of the study was to assess the possible relationships between the P300 event-related brain potential and serotonergic activity in depression. The study was conducted among 45 major depressive inpatients, and serotonergic activity was assessed by prolactin (PRL) response to flesinoxan (a 5-HT1A agonist). Results showed a significant negative correlation between P300 amplitude and PRL response to flesinoxan (r = –0.40, P = 0.007 at Cz; r = –0.47, P = 0.001 at Pz). In contrast, both P300 latency and reaction time were not related to endocrine response. This study supports a role for serotonin-1A in the neurobiological modulation of P300 amplitude.
Serum-antibodies against an organ specific CNS antigen as well as against serotonin and gangliosides (Gm 1) were analysed by ELISA in 34 patients with schizophrenia, ten patients with schizoaffective psychosis and 13 patients with major depressive disorder. Sixty-two patients with various rheumatic disorders and 32 blood donors were included in the study as controls. Sixty-two percent of the 13 patients with major depressive disorder had antibodies to serotonin and 69% to gangliosides, whereas antibody positive sera was only found in 38% of the 34 patients with schizophrenia. The same antibodies were found in only 6% (antibodies to serotonin) and 13% (antibodies to gangliosides) of the 32 blood donors and in a similar frequency in patients with schizoaffective psychosis. Organ specific antibodies to CNS-antigen could not be detected in the psychiatric patient group at any significant level. It is speculated that auto-immune reactions towards a serotonin receptor may be involved in the etiopathogenesis of major depressive disorder.