Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.     

Dopamine and serotonin function in untreated schizophrenia: clinical correlates of the apomorphine and d-fenfluramine tests

This study examined the prolactin (PRL), adrenocorticotropin (ACTH) and cortisol responses to the direct DA receptor agonist apomorphine (APO) and the selective 5HT-releasing agent d-fenfluramine (d-FEN) in 20 untreated inpatients with DSM-IV schizophrenia and without a history of suicide attempt, compared to 23 hospitalized healthy controls. We hypothesized that different patterns of responsiveness of the DA and 5-HT systems might be associated with specific schizophrenic symptom clusters. A positive correlation was observed between pituitary-adrenal response to APO and d-FEN tests (i.e. deltaACTH and deltacortisol) in the overall population and in schizophrenic patients. Pituitary-adrenal response to APO was lower in patients than in normal controls. Moreover, lower pituitary-adrenal response to APO and d-FEN was associated with increased severity of BPRS thought disturbance score. Lower pituitary-adrenal responses to APO (and to a lesser degree to d-FEN) differentiated paranoid from disorganized schizophrenic patients. Neither PRL suppression to APO, nor PRL stimulation to d-FEN were altered in schizophrenic patients. Our results suggest that decreased hypothalamic DA receptor activity (possibly secondary to increased presynaptic DA release) together with relatively decreased 5-HT tone characterize paranoid SCH, while normal hypothalamic DA receptor activity together with relatively increased 5-HT tone characterize the disorganized SCH subtype.     

Anxiety disorders, comorbidity, and suicide attempts in adolescence: a preliminary investigation.

The prevalence of anxiety disorders and associated DSM-III-R diagnoses were measured in a sample of 80 female adolescents aged between 15 to 20 years consulting an outpatient psychiatric service for adolescents. The suicide attempt group (SA) included 40 patients evaluated within 24 h after attempted suicide. This is compared to 40 consecutive patients consulting the same center but without any history of suicide attempt (the no attempt group, NA). The global prevalence of anxiety disorders was similar in both groups (SA: 65% vs. NA: 60%, NS) as was the relative importance of the different disorders in each group, generalized anxiety being the most frequent specific anxiety disorder. The most striking difference between the two groups was in the prevalence of affective disorders in 90% (SA) vs. 32.5% (NA) (P < 0.001), leading to high rates of comorbidity on axis I in the SA group. Of the 24 patients with anxiety disorders who attempted suicide, 21 (95%) fulfilled criteria for associated major depression, compared to five out of 21 (24%) patients with anxiety disorders who had not attempted suicide. Adolescents with anxiety disorders developing major depression are at a high risk for suicide. The depression may be of short duration (less than two weeks) when compared to that of the anxiety disorder (greater than six months). To improve suicide prevention, our findings if confirmed should encourage clinicians to perform a close follow-up of adolescents with anxiety disorders for an early detection of sudden depressive breakdowns.     

5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior.

BACKGROUND: Several lines of evidence suggest a clear relationship between serotonin (5-hydroxytryptamine, 5-HT) hypoactivity and suicidal behavior across several psychiatric diagnoses. Few data are available, however, regarding the possible specific role of 5-HT1A receptors in the biology of suicidality. Therefore, the aim of our study was to use a neuroendocrine strategy to test the hypothesis of a role for 5-HT1A receptors in the biology of suicidal behavior. METHODS: Hormonal (adrenocorticotropic hormone [ACTH], cortisol, prolactin [PRL]) and temperature responses after administration of flesinoxan, a highly potent and selective 5-HT1A receptor full agonist, were assessed in 40 inpatients with major depression, divided into two subgroups (20 suicide attempters and 20 nonattempters), compared with 20 normal control subjects matched for gender and age. RESULTS: Compared with nonattempters, suicide attempters exhibited significantly lower PRL (p = .01), cortisol (p = .014), and temperature (p = .0002) responses. Prolactin (p = .007), cortisol (p = .04), and temperature (p = .00003) responses were also decreased in suicide attempters compared with normal control subjects. In contrast, we did not observe any significant differences in hormonal or temperature responses to flesinoxan between depressed patients without a history of suicide attempt and normal control subjects. CONCLUSIONS: The present study tends to confirm the role of 5-HT and more specifically 5-HT1A receptors in the biology of suicidal behavior in major depression.     

Down-regulation of alpha 2-adrenoceptors involved in growth hormone control in the hypothalamus of infant rats receiving short-term clonidine administration

In infant rats short-term administration of the alpha 2-adrenoceptor agonist, clonidine (CLO), induces refractoriness to the growth hormone (GH)-releasing effect of an acute CLO challenge. CLO reportedly stimulates GH release via increased release of GH-releasing hormone (GHRH) from the hypothalamus. Based on these premises, in this study we investigated the possibility that repeated CLO administration may induce down-regulation of hypothalamic alpha 2-adrenoceptors, involved in GH control, thus prohibiting the GH-releasing effect of the drug. alpha 2-Adrenoceptor binding was determined in different brain regions of 10-day-old rats pretreated for 5 days with CLO (150 micrograms/kg, b.i.d.) and killed 14 h after last CLO administration. [3H]p-Aminoclonidine [( 3H]PAC) was used as the specific ligand of alpha 2-adrenoceptors. Treatment with CLO decreased by about 30% the maximum number of binding sites (Bmax) in areas of the mediobasal hypothalamus (MBH) involved in the stimulatory control of GH secretion, i.e. nucleus periventricularis arcuatus, nucleus ventromedialis hypothalami and nucleus lateralis hypothalami. Reduction of Bmax for [3H]PAC binding was observed also in the nucleus periventricularis hypothalami, an area involved in the inhibitory control of GH secretion and, among extrahypothalamic areas, only in the cortex piriformis. In no brain areas was the affinity constant (Kd) for [3H]PAC binding significantly changed after CLO pretreatment. Binding studies performed with a specific ligand of alpha 1-adrenoceptors, [3H]prazosin, showed that the effect of CLO was specific since no changes in the Bmax or Kd were present in either hypothalamic or extrahypothalamic regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased platelet [3H]paroxetine binding sites in suicide attempters.

Research to date would suggest the possible involvement of the serotonin (5-HT) system in the pathophysiology of suicide. With this study, we aimed to investigate the platelet 5-HT transporter, by means of the specific binding of tritiated paroxetine ([3H]Par), in a sample of 20 suicide attempters recruited at a first-aid service, as compared with healthy control subjects and psychiatric patients with no current or previous history of suicide attempt. The results, showing a decreased number of [3H]Par binding sites in suicide attempters, would suggest the involvement of the presynaptic 5-HT transporter in self-aggressive behavior.     

Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons

Reboxetine is a non-tricyclic antidepressant with selective noradrenergic (NA) reuptake-blocking effects. The effects of acute and sustained administration of reboxetine, on the firing activity of locus coeruleus NA neurons and dorsal raphe 5-HT neurons, were assessed using in vivo extracellular unitary recording in rats anaesthetized with chloral hydrate. Reboxetine (0.1-1.25 mg/kg, i.v.) dose-dependently decreased the firing activity of NA neurons (ED50 = 480 +/- 14 microg/kg). A 2-day treatment with reboxetine at 1.25, 2.5, 5, or 10 mg/kg per day (using osmotic minipumps implanted subcutaneously) produced significant decreases of 52%, 68%, 81%, and 83%, respectively, of NA firing activity. When the reboxetine treatment (2.5 mg/kg per day) duration was prolonged to 7 days, a 66% decrease in NA firing activity was observed which further decreased to 80% after 21 days of treatment. In contrast, 5-HT neuron firing rate remained unaltered following short- and long-term reboxetine treatments. The suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of NA neurons was unchanged in long-term reboxetine-treated rats, but its effect on the firing activity of 5-HT neurons was blunted. The enhancement of NA firing activity by the 5-HT1A agonist 8-OH-DPAT was abolished in long-term reboxetine-treated rats, whereas, the inhibitory effect of the 5-HT2 agonist DOI was attenuated by about three-fold. In conclusion, sustained NA reuptake blockade by reboxetine lead to profound alterations in the function of NA neurons and of 5-HT receptors modulating their firing activity.     

Altered fear circuits in 5-HT(1A) receptor KO mice.

The study of genetically altered mice has been used successfully to determine the influence of different neurotransmitter receptors on fear and anxiety. Mice with a genetic deletion of the serotonin 1A receptor (5-HT(1A)R knockout [KO]) have been shown to be more fearful in a number of behavioral conflict tests, confirming the important role of this receptor in modulating anxiety. Factor analysis of the behavior of WT and 5-HT(1A)R KO mice in the open field test shows that locomotion and anxiety measures segregate independently, supporting the idea that the anxious behavior of the KO mice is not the result of altered locomotion. KO mice also show increased anxiety in the novelty-suppressed feeding task, which differs from the other conflict tests in the motivational drive of the animals. In response to a discrete aversive stimulus, foot shock, the KO mice show increased freezing and increased tachycardia. However, activation of the hypothalamic-pituitary-adrenal axis in response to stress appears to be slightly blunted in the KO animals. Together, these data support the idea that the 5-HT(1A)R modulates an important fear circuit in the brain. The dual function of the 5-HT(1A)R as both a presynaptic autoreceptor, negatively regulating serotonin activity, and a postsynaptic heteroreceptor, inhibiting the activity of nonserotonergic neurons in forebrain structures, has complicated interpretation of the anxious phenotype of these KO mice. A more complete understanding of the function of the 5-HT(1A)R awaits further study of its role in behaving animals using tissue-specific antagonists and novel transgenic mice with tissue-specific expression of the receptor.     

Kinetic studies on uptake of serotonin and noradrenaline into pial arteries of rats

A population of cerebrovascular nerve fibers have recently been found to store serotonin (5-hydroxytryptamine; 5-HT). There is reason to assume that these 5-HT-containing fibers have a sympathetic rather than an intracerebral origin. This was further elucidated in the present study in which the uptake mechanisms of 5-HT and noradrenaline (NA) were characterized and compared in rat pial arteries by measuring the accumulation of [3H]5-HT and [14C]NA under various experimental conditions in vitro. Sympathectomized vessels served as blanks. The uptake into the perivascular sympathetic nerves was dependent on time as well as concentration and was saturable. The Km values were similar, 0.17 microM for 5-HT and 0.15 microM for NA, but the Vmax value was 10 times higher for NA (2.38 and 25 pmol/mg/15 min, respectively). The two amines competed with each other in the sympathetic uptake, as studied by inhibition of the accumulation of one labeled amine by the other nonlabeled amine. Corticosterone, acting on the extraneuronal process, significantly inhibited the 5-HT uptake but had no substantial effect on NA. Reserpine, blocking the intraaxonal vesicular stores, markedly attenuated the accumulation of NA, but not of 5-HT. The selective uptake blocker paroxetine reduced the 5-HT uptake with much higher potency than the NA uptake, whereas desipramine predominantly inhibited NA uptake. The pial 5-HT uptake was not significantly affected by lesion of the raphe complex, whereas it was reduced to half following superior cervical ganglionectomy. The results suggest that the 5-HT present in nerves associated with pial vessels at the base of the brain is taken up through an efficient axonal mechanism, functionally related but not identical to the uptake process for NA.     

Noradrenergic and serotonergic projections to the superior olive: potential for modulation of olivocochlear neurons

The distribution and density of noradrenergic (NA) and serotonergic (5-HT) varicosities in the superior olive (SO) and periolivary region (PO) and their relationship to olivocochlear neurons was studied. Antibodies against 5-HT and the NA precursor enzyme dopamine β-hydroxylase were utilized to examine the density of innervation of SO and PO. To determine the relationship of these varicosities to efferent neurons projecting to the cochlea, olivocochlear neurons were retrogradely labeled with biotinylated dextranamine (BDA). NA and 5-HT varicosities were found adjacent to labeled olivocochlear neuron cell bodies and dendrites. More than 50% of labeled medial olivocochlear (MOC) neurons showed likely contact with NA varicosities and more than 90% of labeled MOC neurons with 5-HT varicosities. There was no apparent difference in the number of lateral olivocochlear (LOC) neurons in close proximity to NA and 5-HT varicosities versus MOCs in close proximity to NA and 5-HT varicosities. Our results suggest that the NA and 5-HT systems are in a position to modulate auditory brainstem processing. The specific relationship of NA and 5-HT varicosities to olivocochlear neurons suggests that one possible level of modulation is prior to signal transduction.     

Neuroendocrine correlates of depression in abstinent heroin-dependent subjects

The functions of the central alpha-adrenergic, serotoninergic and dopaminergic systems were investigated in 28 heroin-dependent subjects 6-8 weeks after detoxification, and in 22 healthy control subjects (group C). Fourteen heroin-dependent subjects with depressive comorbidity (group A), and 14 heroin-dependent subjects without other Axis I and II pathologies (group B) were included among abstinent substance abusers. Norepinephrine (NE) function was evaluated by growth hormone (GH) responses to acute stimulation with clonidine (clon); serotonin (5-HT) function by prolactin (PRL) and cortisol (CORT) responses to acute stimulation with D-fenfluramine (D-fen) and dopamine (DA) function by GH and PRL responses to acute administration of bromocriptine (brom). Central NE activity, as measured by the GH-clon test, seems to be well preserved both in A and B subjects. PRL and CORT responses to D-fen were significantly blunted both in A subjects and in B subjects, in comparison with control subjects (C); the PRL response in A subjects was significantly lower than in B subjects. The DA system of B subjects was found unimpaired; in contrast, a significantly higher GH response to brom in A subjects (depressed) could express D2 post-synaptic receptor hypersensitivity and, therefore, decreased pre-synaptic DA release. In sum, the study of central monoamine function revealed an alteration only of the 5-HT system in detoxified heroin-dependent subjects without psychiatric comorbidity, which might be a trait character of these subjects, possibly involved in the pathogenesis of the disorder. A more significant impairment of 5-HT function and the hypersensitivity of post-synaptic DA receptors in A subjects suggests that specific biological correlates of psychiatric comorbidity may characterize substance abuser subtypes.     

Risk of suicide attempt and suicide death in patients treated for bipolar disorder

OBJECTIVES: To evaluate demographic and clinical predictors of suicide attempt and suicide death in a population-based sample of people treated for bipolar disorder (BD). METHODS: Computerized records were used to identify 32,360 individuals treated for BD at two large prepaid health plans. Suicide attempts were identified using computerized records of outpatient visit diagnoses and hospital discharge diagnoses. Suicide deaths were identified using state death certificate data. RESULTS: Overall event rates were 1.06 per 1,000 person-years for suicide death, 5.6 per 1,000 person-years for suicide attempt leading to hospitalization, and 13.9 per 1,000 person-years for suicide attempt not leading to hospitalization. Men had a significantly lower rate of suicide attempt [hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56-0.83] but a higher rate of suicide death (HR 2.70, 95% CI 1.69-4.31). Suicide attempts were significantly more frequent among younger patients, but suicide deaths did not vary significantly by age. Substance use comorbidity was significantly related to risk of suicide attempt (HR 2.53, 95% CI 2.07-3.09) but not to risk of suicide death (HR 1.02, 95% CI 0.54-1.93). Comorbid anxiety disorder was associated with significantly higher risk of both suicide attempt (HR 1.40, 95% CI 1.14-1.72) and suicide death (HR 1.81, 95% CI 1.09-2.99). CONCLUSIONS: Among people treated for BD, risk of suicide death is significantly related to male sex and comorbid anxiety disorder. The predictors of suicide death differ markedly from predictors of suicide attempt.     

Functional imaging, serotonin and the suicidal brain

The involvement of the serotonergic system in the pathophysiology of suicidal behaviour has been established through indirect and direct research on serotonin and its metabolites and on serotonin transporters and receptors. Indirect research results include a reduced 5-HIAA in cerebrospinal fluid in violent suicide attempters and a blunted increase in prolactin after a fenfluramine challenge. Direct post-mortem research demonstrated an increase in 5-HT2A receptors. Direct in vivo functional imaging with PET or SPECT demonstrated a reduction in 5-HT2A binding index in suicide attempts in anxious and depressed suicide attempters and an increase in 5-HT2A binding in impulsive suicide attempters. These results are in keeping with 5-HT2A binding studies in depressed patients and impulsive animal research. Interestingly, both an increase and a decrease in 5-HT2A binding index seem to normalize with SSRI treatment.     

Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts

OBJECTIVE: To determine if there is a relation to low serum cholesterol, lipoprotein, serotonin or tryptophan levels in patients with depression who have recently attempted suicide. DESIGN: Biochemical and behavioural study. SETTING: Inpatient and outpatient treatment at the Instituto Mexicano de Psiquiatría. PARTICIPANTS: Thirty-three patients with a diagnosis of major depressive episode. Eighteen of these patients had attempted suicide in the month before the start of the study; 15 patients had never attempted suicide. OUTCOME MEASURES: Serum levels of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, serotonin (5-HT) and tryptophan. Scores on Hamilton Depression Rating Scale, Carroll Depression Rating Scale, Beck Hopelessness Scale and Beck Suicide Attempt Severity Scale. RESULTS: There were no significant differences between patients who had attempted suicide and those who had not in terms of serum cholesterol, HDL, LDL and triglyceride levels. Serum levels of 5-HT and tryptophan were significantly lower in patients with depression who had a recent suicide attempt than in those patients who had never attempted suicide. A comparison of patients not taking antidepressant medication found serum 5-HT levels to be more than 3 times lower in those patients with a recent suicide attempt than in patients with no history of suicide attempt. CONCLUSIONS: The study found no difference in lipid profiles between patients who had attempted suicide and those who had not. Low serum levels of 5-HT may increase the risk of suicide attempt in patients who are depressed.     

Anxious-depressive comorbidity: effects on HPA axis and CNS noradrenergic functions

Psychiatric comorbidity is all too common. An important example is the high comorbidity frequency of depressive and anxiety disorders, 25%-50%, much higher than the 5% or less expected by chance. Possible reasons for this comorbidity include definitional, environmental, and biological factors. Few previous studies have assessed, with proper methodology, potential biological changes associated with this co-occurrence. We assessed both hypothalamic-pituitary-adrenocortical axis (HPA) responses to the Trier Social Stress Test and growth hormone (GH) responses to clonidine, a centrally active alpha-2 adrenoreceptor agonist, in 15 persons with major depression without anxiety, 15 with an anxiety disorder without depression, 18 comorbid for anxiety and depression, and 48 individually matched control subjects. Individuals with depression only were normal on both tests, while those with anxiety only had normal HPA responses but blunted GH responses. Comorbid individuals showed elevated HPA responses and only those comorbid persons with anxiety symptoms predominant also showed blunted GH responses. Controls and anxiety-only subjects showed significant correlations between the results of the two tests. This association was disrupted by the presence of depression with or without comorbidity. Comorbidity is fundamental to understanding the pathophysiologies of depression and anxiety.     

Suicidal behaviour in national and international adult adoptees

Background Previous studies have shown an elevated risk for suicidal behaviour in adolescent and young adult international adoptees. Comparisons between national and international adoptees in this respect have been inconclusive. Methods A total of 6,065 international adoptees were compared to 7,340 national adoptees and 1,274,312 non-adopted study subjects, all born between 1963 and 1973 and followed up until 2002 using the National Swedish Registers. Cox regression of person years was used in multivariate analyses to compare risks for suicide death and suicide attempt. Results International adoptees had clearly increased risks for suicide attempt (risk ratio 4.5 [95% confidence interval 3.7–5.5]) and suicide death (3.6 [2.6–5.2]) after adjustments for sex, age and socio-economic factors. National adoptees had lower risks than international adoptees, but had increased risks compared to non-adoptees (suicide attempt, 2.8 [2.2–3.5]; suicide death, 2.5 [1.8–3.3]). Biological parents' morbidity explained approximately one third of the increased risk for national adoptees. Female international adoptees' risk for suicide attempt was elevated to an even greater extent than in male international adoptees, when compared to the general population. Conclusions Clinicians should be aware that an increased risk for suicide and suicide attempts in international adoptees is a topic that is equally relevant to child and adult psychiatry.     

Cardiovascular, neuroendocrine, and sedative responses to four graded doses of clonidine in a placebo-controlled study.

Effects of four doses of the alpha 2-receptor agonist clonidine (CLO) (0.25, 0.5, 1, and 2 micrograms/kg IV) and placebo were studied in seven healthy men who volunteered in a double-blind randomized design in order to delineate possible presynaptic and postsynaptic components in the mechanism of action of CLO. Blood pressure, heart rate, plasma noradrenaline (NOR), plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma growth hormone (GH), and subjective sedation were monitored for a period of 1 hr following infusion of CLO. NOR and MHPG were also analyzed in urine, collected at 1 and 4 hr after the infusions. Dose-dependent decrements were observed in systolic and diastolic blood pressure and plasma NOR levels, and dose-dependent increases in subjective sedation and plasma GH. CLO did not influence plasma MHPG levels, whereas only urinary MHPG excretion was reduced 4 hr after infusion of 2 micrograms/kg CLO. Because no obvious differences between dose-response relations of plasma NOR (believed to be a presynaptic and peripheral effect), blood pressure (believed to be mainly a central presynaptic and postsynaptic effect), and subjective sedation (believed to be a central and probably postsynaptic effect) were observed, our results do not provide simple parameters to discern the multiple mechanisms of action of CLO. However, at a dose of 0.5 micrograms/kg CLO (a dose lower than that generally used) clear effects on plasma NOR, blood pressure, and sedation, but not on plasma GH (a central postsynaptic effect) or urinary MHPG (a presynaptic effect), were observed. When using CLO as a challenge test in psychiatric disorders, a design with 0.5 micrograms/kg CLO, in addition to the traditional 2 micrograms/kg CLO, may provide more information to characterize discrete abnormalities in the noradrenergic system at the level of the brainstem, the pituitary, or the peripheral sympathetic nervous system.     

Neuroendocrine responses to m-chlorophenylpiperazine and L-tryptophan in bulimia.

Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitary-adrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.     

Comorbidity patterns in adolescents and young adults with suicide attempts

The role of comorbidity as a risk for suicide attempts is investigated in a random sample of 3021 young adults aged 14–24 years. The M-CIDI, a fully standardized and modified version of the Composite International Diagnostic Interview, was used for the assessment of various DSM-IV lifetime and 12-month diagnoses as well as suicidal ideation and suicide attempts. Of all suicide attempters, 91% had at least one mental disorder, 79% were comorbid or multimorbid respectively and 45% had four or more diagnoses (only 5% in the total sample reached such high levels of comorbidity). Suicide attempters with more than three diagnoses were 18 times more likely (OR = 18.4) to attempt suicide than subjects with no diagnosis. Regarding specific diagnoses, multivariate comorbidity analyses indicated the highest risk for suicide attempt in those suffering from anxiety disorder (OR = 4.3), particularly posttraumatic stress disorder followed by substance disorder (OR = 2.2) and depressive disorder (OR = 2.1). Comorbidity, especially when anxiety disorders are involved, increases the risk for suicide attempts considerably more than any other individual DSM-IV diagnoses. Received: 17 July 1997 / Accepted: 15 December 1997     

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.