Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders

There is abundant evidence for abnormalities of the norepinephrine (NE) and serotonin (5HT) neurotransmitter systems in depression and anxiety disorders. The majority of evidence supports underactivation of serotonergic function and complex dysregulation of noradrenergic function, most consistent with overactivation of this system. Treatment for these disorders requires perturbation of these systems. Reproducible increases in serotonergic function and decreases in noradrenergic function accompany treatment with antidepressants, and these alterations may be necessary for antidepressant efficacy. Dysregulation of these systems clearly mediates many symptoms of depression and anxiety. The underlying causes of these disorders, however, are less likely to be found within the NE and 5HT systems, per se. Rather their dysfunction is likely due to their role in modulating, and being modulated by, other neurobiologic systems that together mediate the symptoms of affective illness. Clarification of noradrenergic and serotonergic modulation of various brain regions may yield a greater understanding of specific symptomatology, as well as the underlying circuitry involved in euthymic and abnormal mood and anxiety states. Disrupted cortical regulation may mediate impaired concentration and memory, together with uncontrollable worry. Hypothalamic abnormalities likely contribute to altered appetite, libido, and autonomic symptoms. Thalamic and brainstem dysregulation contributes to altered sleep and arousal states. Finally, abnormal modulation of cortical-hippocampal-amygdala pathways may contribute to chronically hypersensitive stress and fear responses, possibly mediating features of anxiety, anhedonia, aggression, and affective dyscontrol. The continued appreciation of the neural circuitry mediating affective states and their modulation by neurotransmitter systems should further the understanding of the pathophysiology of affective and anxiety disorders.     

Cortisol response to dexamethasone and noradrenergic function in depression

Positive correlations between measures of hypothalamic-pituitary-adrenal (HPA)-axis activity and noradrenergic turnover have been reported in depression. To investigate this relationship the authors measured peak postdexamethasone cortisol levels (8 a.m., 4 p.m. and 11 p.m.) and the 24-hour urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) flow in 84 depressed patients. The results show that there is no positive association between those measures of HPA-axis and noradrenergic activity. On the contrary, patients with severe non-suppression (greater than or equal to 10 micrograms/dl or 277 nmol/l) tended to have a lower MHPG-excretion.     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

Serotonergic mechanisms in brains of suicide victims

Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT₁, 5-HT₁ and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [³H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression.     

Anxious and depressive disorders and their comorbidity: effect on central nervous system noradrenergic function.

BACKGROUND: Although comorbidity of anxiety with depression is common, investigations of physiologic abnormalities related specifically to comorbidity are rare. This study examined relationships of DSM-IV-defined depression, anxiety, and their comorbidity to noradrenergic function measured by blunting of the growth hormone (GH) response to the alpha2 adrenoreceptor agonist (and imidazoline receptor agent) clonidine and by blood pressure and symptom responses. METHODS: Fifteen subjects with pure social anxiety or panic disorder, 15 with pure major depression, and 18 with both depression and anxiety were compared with healthy control subjects matched for age and gender. Other factors known to affect GH (weight, menstrual status, prior antidepressant, or other drug exposure) were controlled. RESULTS: Anxiety produced GH blunting, but depression was associated with normal GH responses. The comorbid state did not affect results beyond the impact of anxiety. Preclonidine stress-related GH elevations were observed, to the greatest degree in anxious subjects. Relevant symptom, but not blood pressure, changes were significantly associated with blunting. CONCLUSIONS: With use of pure depression and anxiety groups and careful control of other factors known to affect GH, these results demonstrate central nervous system noradrenergic dysfunction in anxiety disorders. In contrast to less rigorously controlled studies, noradrenergic function in depression was normal.     

Bipolar depression: phenomenological overview and clinical characteristics

OBJECTIVES: There has been increasing interest in the depressed phase of bipolar disorder (bipolar depression). This paper aims to review the clinical characteristics of bipolar depression, focusing upon its prevalence and phenomenology, related neuropsychological dysfunction, suicidal behaviour, disability and treatment responsiveness. METHODS: Studies on the prevalence of depression in bipolar disorder, the comparative phenomenology of bipolar and unipolar depression, as well as neuropsychology and brain imaging studies, are reviewed. To identify relevant papers, a literature search using MEDLINE and PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance in bipolar disorder, and most frequently presents as subsyndromal, minor or dysthymic depression. Compared with major depressive disorder (unipolar depression), bipolar depression is more likely to manifest with psychosis, melancholic symptoms, psychomotor retardation (in bipolar I disorder) and 'atypical' symptoms. The few neuropsychological studies undertaken indicate greater impairment in bipolar depression. Suicide rates are high in bipolar disorder, with suicidal ideation, suicide attempts and completed suicides all occurring predominantly in the depressed phase of this condition. Furthermore, the depressed phase (even subsyndromal) appears to be the major contributant to the disability related to this condition. CONCLUSIONS: The significance of the depressed phase of bipolar disorder has been markedly underestimated. Bipolar depression accounts for most of the morbidity and mortality due to this illness. Current treatments have significant limitations.     

Functional MRI correlates of visuospatial planning in out-patient depression and anxiety

van Tol MJ, van der Wee NJA, Demenescu LR, Nielen MMA, Aleman A, Renken R, van Buchem MA, Zitman FG, Veltman DJ. Functional MRI correlates of visuospatial planning in out‐patient depression and anxiety. Objective: Major depressive disorder (MDD) has been associated with executive dysfunction and related abnormal prefrontal activity, whereas the status of executive function (EF) in frequently co‐occurring anxiety disorders and in comorbid depression–anxiety is unclear. We aimed to study functional MRI correlates of (visuospatial) planning in MDD and anxiety disorders and to test for the effects of their comorbidity. Method: Functional MRI was employed during performance of a parametric Tower of London task in out‐patients with MDD (n = 65), MDD with comorbid anxiety (n = 82) or anxiety disorders without MDD (n = 64), and controls (n = 63). Results: Moderately/severely depressed patients with MDD showed increased left dorsolateral prefrontal activity as a function of task load, together with subtle slowing during task execution. In mildly depressed and remitted MDD patients, in anxiety patients, and in patients with comorbid depression–anxiety, task performance was normal and no activation differences were observed. Medication use and regional brain volume were not associated with altered visuospatial planning. Conclusion: Prefrontal hyperactivation during high planning demands is not a trait characteristic, but a state characteristic of MDD without comorbid anxiety, occurring independent of SSRI use. Disturbances in planning or the related activation are probably not a feature of anxiety disorders with or without comorbid MDD, supporting the current distinction between anxiety disorders and depression.     

Investigating the relationship between plasma neuropeptide-S levels and clinical depression

Purpose: Neuropeptide-S (NPS) is a novel 20-amino acid peptide, mainly expressed in the central nervous system and endocrine tissues. NPS has been linked to anxiety and fear-related behaviors. The association of NPS with depression in a human population has not been previously examined. The aim of the current study was to explore the potential association of NPS with clinical depression and comorbid anxiety.

Materials and methods: Seventy-nine patients diagnosed with major depressive disorder and seventy-eight controls were included in the study. The Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) were used to measure depression and anxiety levels, respectively. Venous blood samples were obtained to measure plasma NPS levels.

Results: There were no statistically significant differences between the patients and controls in terms of sex, marital status, and smoking status. Plasma NPS levels were also not significantly different between the patients and controls. In patients with major depressive disorder, HAM-A and HAM-D scores were significantly higher than those of controls. No correlation was found between plasma NPS levels and age, body mass index (BMI), median HAM-A scores, and median HAM-D scores.

Conclusions: Despite a significantly high level of comorbid anxiety among the patient group, we found no relationship between plasma NPS levels and depressive symptomatology.     

Delusional depression and suicide

After a short survey of the relevant literature, the authors discuss the significance of delusional depression symptoms for suicidality, whereby they do not regard such symptoms alone as a sufficient condition for classifying a delusional patient as suicidal. In a comparison of delusional depressed patients with a non-delusional control group (matched pairs), the former were adjudged to be significantly less suicidal than the control group and did not differ from the control group in regard to suicide frequency.     

Relative activity of metabolic pathways for norepinephrine in endogenous depression

Thirteen patients with endogenous depression, compared to 25 normal controls, had a significantly greater ratio of the urinary excretion of norepinephrine plus its metabolite normetanephrine to either the sum of the two urinary norepinephrine metabolites 3-methoxy-4-hydroxyphenylglycol plus vanillylmandelic acid or to the sum of urinary norepinephrine and all of its metabolites. As urinary levels of norepinephrine and normetanephrine are derived from an extraneuronal metabolic pathway, while levels of 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid are more representative of total norepinephrine metabolism, these results suggest that there is a shift in endogenous depression to extraneuronal metabolic pathways for norepinephrine and its metabolites.     

Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: A double‐blind,randomized, placebo‐controlled study

Depression is one of the most common psychiatric disturbances in Parkinson's disease (PD). Recent reviews have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD. We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants differ in their short‐term efficacy, because the time to onset of therapeutic benefit remains an important criterion in depression. The short‐term efficacy (after 14 and 30 days) of two antidepressants (desipramine, a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram, a SSRI) was assessed in a double‐blind, randomized, placebo‐ controlled study of 48 nondemented PD patients suffering from major depression. After 14 days, desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale (MADRS) score, compared with citalopram and placebo. Both antidepressants produced significant improvements in the MADRS score after 30 days. Mild adverse events were twice as frequent in the desipramine group as in the other groups. A predominantly noradrenergic tricyclic antidepressant induced a more intense short‐term effect on parkinsonian depression than did an SSRI. However, desipramine's lower tolerability may outweigh its slight short‐term clinical advantage. © 2008 Movement Disorder Society     

Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors

Severity of depression, as reflected by total scores on depression rating scales, has been established as one of several major sources of variance associated with hypothalamic-pituitary-adrenal axis dysregulation in patients with major depressive disorder. To determine which of the symptoms comprising clinically defined severity of illness contribute most to this relationship, we studied the associations between postdexamethasone plasma cortisol levels and components of the Hamilton Rating Scale for Depression (HRSD) in 114 patients with major depressive disorder. At pretreatment baseline, severity of depression was modestly but significantly correlated with postdexamethasone plasma cortisol; a large part of this relationship was associated with the anxiety components of the HRSD. When relationships between postdexamethasone plasma cortisol and severity measures were studied longitudinally during treatment, this contribution of the anxiety items persisted. The anxiety associated with depression appears to be a major clinical factor associated with the hypothalamic-pituitary-adrenal axis dysregulation in major depressive disorder.     

Comorbid depression and anxiety spectrum disorders

The relationship between depression and anxiety disorders has long been a matter of controversy. The overlap of symptoms associated with these disorders makes diagnosis, research, and treatment particularly difficult. Recent evidence suggests genetic and neurobiologic similarities between depressive and anxiety disorders. Comorbid depression and anxiety are highly prevalent conditions. Patients with panic disorder, generalized anxiety disorder, social phobia, and other anxiety disorders are also frequently clinically depressed. Approximately 85% of patients with depression also experience significant symptoms of anxiety. Similarly, comorbid depression occurs in up to 90% of patients with anxiety disorders. Patients with comorbid disorders do not respond as well to therapy, have a more protracted course of illness, and experience less positive treatment outcomes. One key to successful treatment of patients with mixed depressive and anxiety disorders is early recognition of comorbid conditions. Antidepressant medications, including the selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, are highly effective in the management of comorbid depression and anxiety. The high rates of comorbid depression and anxiety argue for well-designed treatment studies in these populations. Depression and Anxiety 4:160–168, 1996/1997. © 1997 Wiley-Liss, Inc.     

精神疾病患者血小板5-羟色胺水平与自杀

目的：探讨精神分裂症和抑郁症患者血小板5-羟色胺（5-HT）水平与自杀的关系。方法：对66例精神分裂症患者、61例抑郁症患者和26名正常对照组,采用高效液相-电化学检测法测定血小板5-HT水平并作5年的随访。结果：精神分裂症自杀组血小板5-HT水平显著高于正常对照组,抑郁症患者血小板5-HT水平显著低于正常对照组。在入组后的5年间有26例再次发生自杀,再次自杀组的血小板5-HT水平显著低于未再自杀组。结论：低血小板5-HT水平可能对预测精神疾病患者未来的自杀有一定的参考价值。     

Fluoxetine for poststroke depression ——A randomized placebo controlled clinical trial

BACKGROUND: Studies have demonstrated that poststroke depression(PSD) may be related with the disequilibrium between noradrenaline and 5-hydroxytryptamine (5-HT) caused by cerebral injury. The injured regions involve noradrenergic and 5-hydroxytryptaminergic neurons as well as conduction pathway. The levels of noradrenaline and 5-HT would be decreased. OBJECTIVE: To observe the effect of fluoxetine on preventing against PSD and recovery of neurologic function, and analyze the relationship of fluoxetine and the 5-HT level. DESIGN: A randomized controlled clinical trial. SETTING: Department of Neurology, First Hospital Affiliated to Soochow University. PARTICIPANTS: Ninety consecutive patients, 47 female and 43 male, were recruited who admitted to hospital for recent stroke in the Department of Neurology, First Affiliated Hospital of Soochow University between September 2003 and February 2005. Subjects were aged (64±7 ) years, ranging from 47 to 79 years old. They all met the diagnosis criteria of various cerebrovascular diseases formulated in the 4th National Cerebrovascular Disease Conference and confirmed as stroke by skull CT or MRI; The time from onset to tentative administration was less than 7 days; The patients had clear consciousness, without obvious language disorder. They were randomized into treatment group (n =48) and placebo group (n =42). METHODS: ①All the patients were given routine treatment according to treatment guideline of cerebrovascular disease after admission. Patients in the treatment group and placebo group received 20 mg/d fluoxetine and placebo (component: vitamin C) for 8 weeks, respectively. ② Neurologic deficit was assessed according to 24-item Hamilton Rating Scale for Depression (HAMD) and Activity of Daily Living Scale (ADL) before and at 2,4 and 8 weeks after test, separately; Meanwhile, the levels of platelet 5-HT and plasma 5-HT were determined. Grading criteria of HAMD intergral depression: non-depression < 8 points; mild depression 8–20 points; moderate depression 21–35 points; severe depression > 35 points. ADL was assessed with Barthel index score (full mark 100 points). Higher points indicated better incidence and smaller dependence. Neurologic deficit score was made according to scoring criteria of neurologic deficit formulated in 1995 4th National Cerebrovascular Disease Conference: a score of 0–15 indicated a mild focal neurologic deficit, a score of 16–30 a moderate focal neurologic deficit, and a score of 31–45 a severe focal deficit. MAIN OUTCOME MEASURES: Scores of HAMD, ADL and neurologic deficit, and levels of plasma and platelet 5-HT of patients from 2 groups before, 2,4 and 8 weeks after test. RESULRS: Seventy-three of 90 randomized patients participated in the final analysis. In the treatment group, 11 patients dropped out due to insufficient clinical response (n =4), somatic side effects (n =2), intervening medical illness (n =1), hypomania (n =3), and other reasons (n =2). In the placebo group, 6 patients existed due to insufficient clinical response (n =2), somatic side effects (n =1) and other reasons (n =3). ① Before treatment, there were no significant differences in scores of HAMD, DAL and neurologic deficit in patients between two groups (P > 0.05). After 8 weeks of treatment, the scores of HAMD, DAL and neurologic deficit in the treatment group were significantly different from those in the placebo group (12.6±5.3 vs. 16.3 ±3.7; 8.6±6.4 vs. 11.2±6.4; 60.4±12.5 vs. 52.3±13.5, P < 0.01). ② After 8 weeks of treatment, platelet 5-HT level of patients in the treatment group was significantly lower than that in the placebo group [(325.3± 110.5) mg/L vs. (653.6±138.4) mg/L, P < 0.05], while there were no significant differences in plasma 5-HT between two groups (P > 0.05). CONCLUSION: Early fluoxetine treatment obviously retards PSD. The increase of platelet 5-HT level promotes the recovery of neurologic function.     

Suicide rate,prevalence of diagnosed depression and prevalence of working physicians in Hungary

Based on the well-known relationship between depression and suicide, we investigated the regional distribution of the suicide rate, rate of diagnosed depression and prevalence of working physicians in Hungary. A strong significant positive correlation was found between the rate of working physicians and rate of diagnosed depression, and both parameters showed a strong significant negative correlation with the suicide rate. The more physicians per 100,000 inhabitants, the better is the recognition of depression and the lower is the suicide rate in the given region. The rate of working doctors was significantly higher in the counties located in western Hungary, which may have a role in the lower suicide mortality in this area of the country.     

Attempted suicide and depression in schizophrenia

The relationships between symptoms and both prior suicide attempts and current suicidal thinking were examined in a sample of schizophrenics at 2 points in time. Fifty subjects meeting DSM-III criteria for schizophrenia were assessed within 1 week of admission, and 41 were reassessed at a 6-month follow-up. On admission, prior suicide attempts were significantly associated with current depression, female sex, lower education and more frequent hospitalization. The association with depression remained significant at follow-up. In addition, current suicidal thinking was associated with depression at both times but also with negative symptoms at time 1 and delusions and hallucinations at time 2. These findings confirm and strengthen prior reports of an association between depression and attempted suicide.     

Serotonergic influence on the growth hormone response to clonidine in rat

Summary Administration of the alpha₂-adrenoceptor agonist clonidine induces growth hormone (GH) release in rat and man. In the present study it is shown that the GH response to clonidine is weaker in rats exposed to depletion of both noradrenaline and serotonin (by means of reserpine or the combined treatment of FLA-63 and PCPA) than in animals exposed to noradrenaline depletion (by means of FLA-63) only. The possibility that an impaired serotonergic neurotransmission contributes to the blunted GH responses to clonidine observed in patients suffering from endogenous depression is discussed.     

Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain

This paper presents two experiments that continue efforts to determine the neurochemical changes responsible for stress-induced behavioral depression. These expriments measured active motor behavior in a swim tank as well as levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in various brain regions of rats after the animals had (a) been exposed to electric shocks they could control (Avoidance-escape condition), or (b) received the same shocks with no control over them (Yoked condition), or (c) received no shock (No-shock condition). In the first experiment, measures were taken 90 min after the shock session ended. In the swim test, Yoked animals showed a depression of active behavior relative to the other groups. From measures of monoamine levels, the change found to be most closely related to this post-stress behavioral depression was in NE in the locus coeruleus (LC), where Yoked animals showed a considerable depletion of NE. In the second study, the same measures were taken 48 h and 72–96 h after the stress session. Yoked animals tested at 48 h post-stress showed motor depression, but those tested after 72–96 h did not. NE in the LC was significantly depleted in Yoked animals tested at 48 h post-stress but showed only slight (and non-significant) depletion in those tested 72–96 h post-stress. These results, together with others, suggest that large stress-induced depletion of NE in the LC is involved in mediating behavioral depression brought about by severe stress. It is further suggested that the time course for behavioral recovery and for the disappearance of NE depletion in the LC that was seen in Yoked animals after stress parallels the time course previously reported by other investigators for induction of catecholamine-synthesizing enzymes — tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) — in the LC, so that induction of TH and DBH activity may be a neurochemical mechanism to bring about recovery from poststress behavioral depression.