Serotonergic and noradrenergic function in depression: clinical correlates

The present study was conducted in order to investigate the relationships between central noradrenergic (NA) and serotonergic (5-HT) function and clinical characteristics of a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We measured growth hormone response (ΔGH) to clonidine (CLO) (an α2 NA agonist), as an index of central NA function, and prolactin response (APRL) to d-fenfluramine (d-FEN) (a specific 5-HT releaser/uptake inhibitor), as an index of central 5-HT function, in 53 medication-free depressed inpatients. On the basis of their CLO and d-FEN test responses, patients were classified into 4 groups. Group 1 (blunted ΔPRL(d-FEN) alone [11 %]) was characterized by a recent violent suicide attempt, a high degree of medical damage, and mild anxiety. Group 2 (blunted ΔGH(CLO) alone [32%]) was characterized by an absence of a history of suicide attempt and by severe anxiety. Group 3 (combination of blunted ΔGH(CLO) and APRL(d-FEN) [18%]) was characterized by a history of suicide attempts, total duration of the illness of over W years, age over 40 years, and more than 3 previous hospitalizations. Group 4 (no abnormality [39%]) had no specific clinical profile. These results suggest that, in depression, specific psychopathological features may be linked to 5-HT and/or NA dysfunction. However, our results also suggest that NA and/or 5-HT dysfunction are less likely to be the primary cause of mood disorders but are more indicative of failure of compensatory mechanisms involved in affective homeostatic processes.     

Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies

Objectives:  Serotonin (5-hydroxytryptamine; 5-HT) and endocrine abnormalities have been repeatedly reported in bipolar disorders (BD). Useful methods to investigate 5-HT responsivity, and the interaction with neuroendocrine functioning, are provided by acute 5-HT challenge and depletion paradigms. In this review 5-HT challenges are limited to paradigms that stimulate 5-HT activity in BD.
Methods:  Literature was searched for in electronic libraries: MEDLINE and PSYCHLIT, period 1966–2001. Papers describing effects of an acute 5-HT challenge on neuroendocrine functioning in BD patients were selected.
Results:  Review of the literature revealed 15 studies: five papers described the effects of 5-HT challenges in manic BD patients, four papers in euthymic BD and seven in depressed BD patients. The reviewed 5-HT challenge paradigms are acute administration of oral and intravenous (i.v.) dosage of d,l-fenfluramine, tryptophan, 5-hydroxytryptophan, ipsapirone and buspirone. There were no papers which investigated neuroendocrine effects of m-chlorophenylpiperazine, clomipramine and citalopram in BD patients and were therefore not reviewed.
Conclusions:  The literature on 5-HT challenge procedures in BD shows evidence for a blunted prolactin (PRL) in mania and depression as well as a blunted cortisol in euthymic BD patients. This suggests that in both mania and depression similar changes in the 5-HT system are involved. It is speculated that blunting of cortisol responses in euthymic BD patients may be a result of chronically altered 5-HT functioning, whereas changes in PRL release following 5-HT challenges reflect more state-dependent changes in 5-HT activity. The 5-HT responsivity in BD patients has also been associated with pharmacological treatment, suicidal behaviour, weight loss and age. Recommendations for future research are given.     

Alpha-1- and 2-adrenoceptor subsensitivity in siblings of opioid addicts with personality disorders and depression

Noradrenergic receptor sensitivity of 16 healthy male siblings of heroin addicts and of 8 age and sex-matched controls was examined by administering a clonidine stimulation test and by measuring the resulting growth hormone (GH) (alpha-2-adrenoceptors) and beta-endorphin (β-endorphin) (alpha-1-adrenoceptors) responses. Siblings were divided into two groups: A = siblings of heroin addicts with personality disorders and high aggressivity and B = siblings of heroin addicts without mental disorders. The GH and β-endorphin responses to clonidine were blunted in group A subjects compared with controls and normal in group B.     

Serotonergic and dopaminergic neuroendocrine responses of male depressive patients before and after a therapeutic ECT course

Background: Electroconvulsive therapy (ECT) is an effective treatment for major depressive illness, even for patients who do not respond to antidepressant drugs. According to the prevailing neurophysiological hypotheses for depression, it can be expected that an ECT therapeutic course modulates the responsivity of central neurotransmitter systems, but the results up to now have been inconclusive. To test such hypotheses, we studied possible changes in the serotonergic and in dopaminergic systems' responsivity in 11 male patients with major depression by performing neuroendocrine challenge tests before and after a therapeutic ECT course. Methods: Serotonergic responsivity was assessed by measuring the prolactin and cortisol responses to i. v. administration of the serotonin uptake inhibitor clomipramine (CMI test), and dopaminergic responsivity by measuring the prolactin responses to the dopamine receptor blocker haloperidol (HAL test), administered intramuscularly. The prolactin and cortisol responses during the first and the last ECT of the course (8 to 13 sessions) were also assessed. The CMI and HAL tests were also performed in 13 male healthy subjects. Results: The prolactin responses to CMI were significantly blunted in the patient group compared to the control group, and remained unaltered at the end of the ECT course, although the depressive symptomatology was substantially reduced from 27.8 ± 7.1 to 4.8 ± 2.3 points in the Hamilton Depression Rating Scale. The cortisol responses to CMI were blunted before the ECT course compared to controls, but not after the course: there was a moderate increase of cortisol at + 30 min in the CMI test after the ECT course compared to that before ECT (p = 0.05). The prolactin and cortisol responses to the electrical stimulus during the first and the last ECT were identical. Conclusions: The strong therapeutic effect of ECT in depression, observed already at the end of the course, is not a result of considerable modifications in central serotonergic or dopaminergic responsivity, as revealed by the neuroendocrine challenge tests and the hormone responses to the electrical stimulus. The enhancement of the cortisol responses to CMI after the course may indicate a moderate increase in 5-HT1A receptor responsivity. Received: 5 March 2002 / Accepted: 15 July 2002     

HPA axis function in depression and dementia: A review

This article reviews recent advances in the understanding of hypothalamic-pituitary-adrenal (HPA) dysfunction in depression and dementia. Although the dexamethasone suppression test (DST) has proved disappointing as a diagnostic test, more recent tests of HPA axis function have not yet been adequately investigated in this regard. There is mounting evidence from both animal and human studies that a complex interrelationship exists between mood, age, cognitive function, brain structure and HPA axis dysfunction. To explore this relationship further, studies combining clinical, neuroimaging and neuroendocrine investigation are required.     

Effect of pindolol on hormone secretion and body temperature: Partial agonist effects

Summary Pindolol has been shown to be a partial agonist at 5-HT_1a receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT_1a partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT_1a receptors in man. To determine if pindolol has 5-HT_1a agonist as well as antagonist effects in man, pindolol, 30 mg, p.o. and placebo, were given single blind in random order to 23 normal men with indwelling venous catheters and its effects on hormone secretion and body temperature noted. Pindolol significantly increased basal plasma cortisol concentrations, whereas it decreased plasma prolactin (PRL) concentrations and body temperature. The increase in plasma cortisol due to pindolol suggests a 5-HT_1a agonist action and is consistent with a 5-HT_1a partial agonist mechanism in man whereas the PRL effects are consistent with an antagonist action at 5-HT_1a receptors. The effects of pindolol on plasma cortisol concentration and body temperature were significantly negatively correlated. Furthermore, these results indicate significant differences in the 5-HT_1a -dependent regulation of PRL and the hypothalamo-pituitary-adrenal (HPA) axis and body temperature, and suggest that human basal PRL secretion is tonically stimulated by a 5-HT_1a mechanism whereas the HPA axis and body temperature are not. Since rodent studies suggest differences in 5-HT_1a receptor sensitivity between males and females, the results reported here need to be replicated in females. These differences in the effect of pindolol are discussed in terms of receptor reserve theory.     

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.     

Psychocardiological disorder and brain serotonin after comorbid myocardial infarction and depression: an experimental study

Objectives We investigated whether trimetazidine pretreatment can regulate central and peripheral serotonin (5-HT) in rats of myocardial infarction (MI) combined with depression.

Methods Forty rats were randomly assigned to a sham operation group (n = 10) and a disease model group (n = 30). The sham operation group was pretreated with normal saline for 4 weeks. The disease model group was randomly assigned further into a negative control subgroup, a positive control subgroup, and a treatment subgroup — the groups received saline, sertraline, and trimetazidine pretreatment, respectively, for 4 weeks, then the rats were subjected to MI combined with depression. 5-HT concentrations in the serum, platelet lysate, and cerebral cortex lysate were analyzed with ELISA.

Results The levels of serum 5-HT and platelet 5-HT were significantly lower in negative control subgroup than the sham operation group (P < 0.05), but there was no significant difference in brain 5-HT (P > 0.05). Compared with the negative control subgroup, the levels of serum 5-HT and platelet 5-HT in the positive control subgroup and treatment subgroup were significantly higher (P < 0.05). The levels of 5-HT in brain of the positive control subgroup and treatment subgroup were significantly lower than those in the negative control subgroup (P < 0.05).

Conclusions Trimetazidine pretreatment can increase serum and platelet 5-HT levels in rats with MI and depression and decrease 5-HT levels in brain tissue. This regulatory effect on central and peripheral 5-HT suggests a role for trimetazidine in the treatment of psychocardiological diseases.     

Neuroendocrinological study of opioid and serotoninergic systems in migraine patients

PRL response to morphine in a group of migraine subjects was studied in the baseline condition and after neuroendocrinological inhibition and stimulation tests. No significant differences were found in comparison with control subjects. This demonstrated the integrity of the opioid system and serotoninergic pathways in migraine subjects.

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Sommario In un gruppo di soggetti emicranici è stata studiata la risposta in prolattina alla morfina in condizioni basali e con tests neuroendocrinologici di stimolazione ed inibizione. Non si sono riscontrate significative differenze nei confronti dei soggetti di controllo. Si è cosi documentata l'integrità del sistema degli oppiati endogeni e della via serotoninergica nei pazienti emicranici.

     

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.     

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Escape from dexamethasone suppression: Possible role of an impaired inhibitory opioid mechanism

1. 1. Several lines of evidence indicate that the activity of the hypothalamus-pituitary-adrenal (HPA) axis in depression is disinhibited.

2. 2. Escape from dexamethasone suppression, although not limited to is more frequent in patients with endogenous depression compared to normals or patients with other psychiatric diagnoses.

3. 3. Norepinephrine, serotonin and acetylcholine have been implicated in the pathophysiology of this neuroendocrine abnormality.

4. 4. Morphine, 5 mg intravenously, suppressed Cortisol secretion in healthy volunteers (n = 4) and the majority of 32 psychiatric inpatients.

5. 5. However, patients with endogenous depression abnormal dexamethasone suppression test results show early resumption (escape) of cortisol secretion following the initial suppression induced by morphine.

6. 6. It is concluded that the pathophysiology of this neuroendocrine abnormality is not limited to classical neurotransmitter-HPA axis interaction but that it also involves opioid inhibitory mechanisms.

Serotonergic neurotransmission in early Parkinson's disease: A pilot study to assess implications for depression in this disorder

Abstract

Objectives. Depression, a disease usually accompanied by a serotonergic deficit, has been observed in about 40% of patients suffering from Parkinson's disease (PD). Thus, a serotonergic dysfunction in PD can be assumed. We aimed to investigate the interaction between serotonergic (5-HT) and dopaminergic activity in early PD. We hypothesized a serotonergic as well as a dopaminergic deficit in PD patients. We also assumed a correlation between these neurotransmitters indicating a relationship between dopaminergic and serotonergic function in PD. Methods. Nine unmedicated PD patients before and 12 weeks after l-dopa treatment and nine healthy subjects were examined using the loudness dependence of auditory evoked potentials (LDAEP), a promising indicator of central serotonergic function. Dopaminergic transporters (DAT) were collected using ¹²³I-FP-CIT and single photon emission computer tomography (SPECT). LDAEP values were correlated with ¹²³I-FP-CIT SPECT data. Results. A significant difference between LDAEP of controls and patients (P= 0.05) suggested lower serotonergic activity in PD. Twelve weeks after initiation of l-dopa treatment this difference was lost between patients and controls (P= 0.20). There was a trend towards a correlation between LDAEP and DAT (r= 0.65; P = 0.057) of the unmedicated patients, suggesting a low serotonergic activity may be related to a dopamine deficit in PD. Conclusions. Our results support the hypothesis that serotonergic neurotransmission is decreased in untreated PD and suggest that a low serotonergic activity may be related to the dopamine pathology in PD. This could be related to the high prevalence of depression in PD.     

Thyrotropin releasing hormone test in unipolar depressed patients and controls: relationship to clinical and biologic variables

We compared unipolar depressed patients (n = 31) with controls (n = 38) for their responses to the thyrotropin releasing hormone (TRH) test. Depressed patients showed significantly smaller thyrotropin stimulating hormone (TSH) responses to TRH which correlated negatively with post-dexamethasone plasma cortisol levels. Depressed patients also showed significant negative correlations between delta max TSH and urinary outputs of norepinephrine and normetanephrine with similar trends with plasma levels of norepinephrine and 3-methoxy-4-hydroxyphenylglycol. Patients who showed a blunted TSH response, compared with those who did not, had significantly lower platelet serotonin uptake values. These results suggest that the blunted TSH response to TRH seen in depression may be associated with dysregulation of the cortisol, noradrenergic and serotonin systems.     

Neurotransmitter metabolites and endocrine responses in depression

1. Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3–4-dihydroxyphenylethylene-glycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder.

2. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 < p < .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH.

3. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.     

抑郁症患者治疗前后血浆皮质醇水平的变化

目的:探讨抑郁症患者治疗前后血浆皮质醇水平的变化。方法:对160例抑郁症患者给予抗抑郁药治疗6周,分别于治疗前及治疗后进行汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)评估及血浆皮质醇水平检测。结果:本组治疗前后HAMD总分分别为(24.98±5.10)和(7.57±5.61);HAMA总分分别为(20.62±6.90)和(6.21±5.17);血浆皮质醇水平分别为(407.34±144.29)nmol/L和(354.64±137.13)nmol/L。治疗后HAMD总分、HAMA总分及血浆皮质醇水平较治疗前明显下降(P均<0.001);不同性别间血浆皮质醇水平差异无统计学意义(P>0.05);血浆皮质醇变化值与HAMD、HAMA减分率不相关(r=0.084,r=0.049;P均>0.05)。结论:抗抑郁药物治疗可显著降低抑郁症患者血浆皮质醇水平。     

Oscillatory serotonin function in depression

Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 min for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting‐state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy, 3,4‐methylenedioxy‐N‐methylamphetamine) users because of their chronically diminished 5HT function compared with non‐MDMA polysubstance users (Karageorgiou et al., 2009). Compared with a non‐MDMA using cohort, MDMA users showed diminished fMRI intra‐regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated. Synapse 67:801–820, 2013 . © 2013 Wiley Periodicals, Inc.     

The effect of amphetamine on plasma cortisol in patients with endogenous and non-endogenous depression

Amphetamine sulphate (0.1 mg/kg, i.v.) produced no consistent change in plasma cortisol levels in 21 depressed patients. Seven patients with endogenous depression (melancholia) were matched with seven patients with non-endogenous depression; there was no difference in the cortisol response to amphetamine between these two groups.     

The association of major depression, conduct disorder, and maternal overcontrol with a failure to show a cortisol buffered response in 4-month-old infants of teenage mothers.

BACKGROUND: Adolescent pregnancy can be associated with major depression (MD) and conduct disorder (CD). Some infants of adolescent mothers are prenatally exposed to these factors, which may result in heightened risk for perturbations of their stress systems. Between 2 and 4 months, a normal shift occurs in the adrenocortical system in which we observe a marked decrease in infant cortisol response when facing mild stressors. This study aimed to explore whether MD (lifetime, during pregnancy, postpartum), CD, and maternal overcontrol are associated with increased cortisol reactivity in 4-month-old infants of teenage mothers. METHODS: Using arm restraint as a stressor, morning salivary cortisol was taken prestressor and poststressor in 212 infants during a laboratory visit. Major depression and CD were measured with the computerized National Institute of Mental Health Diagnostic Interview Schedule (NIMH-DIS), postpartum depressive mood was measured with the Edinburgh Postnatal Depression Scale, and overcontrol was observed with the CARE-Index. RESULTS: Independent of the predictors, there was a dampened cortisol response. Infants of mothers with lifetime MD and of average to highly overcontrolling mothers showed increased cortisol reactivity. Conduct disorder and cortisol levels were not associated. CONCLUSIONS: Future studies should detect whether the absence of a dampened cortisol response in infants whose mothers have lifetime MD or display overcontrolling parenting is stable over time.