Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes

BACKGROUND: Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin2 BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin. METHODS: Regional 5-HTT BP was measured in 20 nonsmoking medication-free (> or =3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [11C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale. RESULTS: No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F(1,26), 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]). CONCLUSIONS: Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.     

Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907

OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.     

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.     

Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment

BACKGROUND: Pharmacological and postmortem investigations suggest that patients with major depressive disorder have alterations in function or density of brain serotonin1A (5-HT1A) receptors. The aim of the present study was to use positron emission tomography with the selective 5-HT1A receptor antagonist [11C]WAY-100635 to measure 5-HT1A receptor binding in depressed patients before and during treatment with selective serotonin reuptake inhibitors. METHODS: Positron emission tomographic scans with [11C]WAY-100635 were performed on 25 patients with major depressive disorder. These included 15 unmedicated depressed patients. Ten of these unmedicated patients were scanned again during selective serotonin reuptake inhibitor treatment. A further 10 patients with major depressive disorder were scanned on one occasion only while taking selective serotonin reuptake inhibitors. Comparisons were made with [11C]WAY-100635 positron emission tomographic scans in 18 healthy volunteer subjects. Region of interest analysis and statistical parametric mapping were performed on binding potential images generated using a reference tissue model. RESULTS: Binding potential values were reduced across many of the regions examined, including frontal, temporal, and limbic cortex in both unmedicated and medicated depressed patients compared with healthy volunteers. Binding potential values in medicated patients were similar to those in unmedicated patients. CONCLUSIONS: Major depressive disorder is associated with a widespread reduction in 5-HT1A receptor binding. This reduced 5-HT1A receptor binding was not changed by selective serotonin reuptake inhibitor treatment.     

Are dysfunctional attitudes in depressive disorder trait or state dependent?

The aim of this study was to investigate whether euthymic patients in remission on lithium prophylaxis score higher on the Dysfunctional Attitude Scale (DAS) than healthy subjects, thus indicating a trait quality of dysfunctional attitudes in unipolar depression. A total of 79 patients with recurrent unipolar depressive episodes and 79 individually matched healthy controls were compared using a Swedish version of the DAS. The results indicate that DAS score is a state-dependent variable in depressive disorder.     

Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women

OBJECTIVE: This study investigated the effect of estrogen on brain serotonin 2A (5-HT(2A)) receptors in postmenopausal women and whether there was any correlation of receptor changes with cognition and mood. METHOD: Ten postmenopausal subjects underwent positron emission tomography measurements of 5-HT(2A) receptor binding with [(18)F]deuteroaltanserin before and after estrogen replacement therapy. RESULTS: 5-HT(2A) receptor binding was significantly increased after estrogen replacement therapy in the right prefrontal cortex (right precentral gyrus [Brodmann's area 9], inferior frontal gyrus [Brodmann's area 47], medial frontal gyrus [Brodmann's area 6, 10] and the anterior cingulate cortex [Brodmann's area 32]). In the inferior frontal gyrus [Brodmann's area 44]), receptor up-regulation was correlated with change in plasma estradiol. Verbal fluency and Trail Making Test performance, but not mood, were significantly improved by estrogen without correlation with receptor changes. CONCLUSIONS: Estrogen increases 5-HT(2A) receptor binding in human prefrontal regions.     

Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography.

BACKGROUND: Serotonin 5-HT(2A) receptors play an important role in the regulation of many functions that are disturbed in patients with major depressive disorder. Postmortem and positron emission tomography studies have reported both increased and decreased 5-HT(2A) receptor binding in different limbic and paralimbic regions. METHODS: We conducted a quantitative 5-HT(2A) receptor binding study using positron emission tomography and [(18)F]altanserin of four regions hypothesized to have altered levels of 5-HT(2A) receptors in major depressive disorder. Using a four-compartment model, the 5-HT(2A) receptor distribution was estimated by calculating the regional [(18)F]altanserin k(3)/k(4) ratio in which k(3) is the rate of binding to the receptor and k(4) is the rate of dissociation from the receptor. Forty-six antidepressant-free patients with major depressive disorder and 29 healthy control subjects were enrolled. RESULTS: 5-HT(2A) receptor binding in the hippocampus was reduced by 29% in depressed subjects (p =.004). In other regions, 5-HT(2A) receptor binding was decreased (averaging 15%) but not significantly. Both groups had similar age-dependent decreases in 5-HT(2A) receptors throughout all brain regions. CONCLUSIONS: Altered serotoninergic function in the hippocampus is likely involved in the disturbances of mood regulation in major depressive disorder, although the specific role of the 5-HT(2A) receptor changes is still unclear.     

Depressive and anxiety symptoms, dysfunctional attitudes and social aspects in irritable bowel syndrome and inflammatory bowel disease

OBJECTIVE: Biopsychosocial models for both organic and functional gastrointestinal (GI) disorders have been described in the recent literature. The objective of this study was to give further data to this model by assessing stressful life events, social support, psychopathological symptoms, and dysfunctional attitudes in irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and healthy subjects. METHOD: Age- and gender-matched IBS and IBD patients presenting at a tertiary care gastroenterological center completed self-reported questionnaires on stressful life events, social support, depressive and anxiety symptoms and dysfunctional attitudes. For comparative purposes, data from an age- and gender-matched healthy control group were obtained. RESULTS: No significant differences were found between the groups regarding stressful life events and social support. Both patient groups had higher depressive and anxiety symptoms compared to healthy subjects, and IBS patients had higher depressive scores compared to IBD patients. IBS patients had more dysfunctional attitudes compared to both IBD and healthy subjects, while IBD and healthy subjects did not differ on dysfunctional attitudes. CONCLUSIONS: GI patient status is associated with depressive and anxiety symptoms, in addition IBS patients have more severe depressive symptoms and depressogenic dysfunctional attitudes. The fact that functional GI patients are characterized by more severe psychological, but not social parameters, supports the hypothesis that IBS might be related to the range of depressive disorders.     

Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia

OBJECTIVE: Inhibition mediated by gamma-aminobutyric acid at the axon initial segment of pyramidal neurons appears to be altered in the prefrontal cortex in schizophrenia. This study examined the densities and laminar distribution of axon initial segments labeled with an antibody against the serotonin(1A) (5-HT(1A)) receptor, which also mediates inhibitory regulation of pyramidal neurons, in subjects with schizophrenia. METHOD: The densities and laminar distribution of axon initial segments with 5-HT(1A)-like immunoreactivity were assessed in postmortem tissue from the prefrontal cortex (Brodmann's area 46) of 14 matched triads of subjects with schizophrenia, subjects with major depressive disorder, and comparison subjects with no psychiatric disorder. RESULTS: The relative densities of the labeled axon initial segment in both the superficial and the deep cortical layers did not differ across the three subject groups. CONCLUSIONS: The findings do not support a role for altered serotonin transmission by means of the 5-HT(1A) receptor in dysfunction of prefrontal cortex pyramidal neurons in schizophrenia.     

Dysfunctional attitudes and cognitive schemas in bipolar manic and unipolar depressed outpatients: implications for cognitively based psychotherapeutics

Dysfunctional thought patterns are presumed to underlie cognitive biases in mood disorder patients. However, few studies have compared dysfunctional thought patterns in bipolar manic and unipolar depressed patients. Cognitive schemas and dysfunctional attitudes were evaluated using the cognitive checklist for mania and Dysfunctional Attitudes Scale (DAS) in 34 bipolar manic, 35 unipolar depressed, and 29 nonpsychiatric control subjects. Unipolar depressed subjects had significantly higher total DAS scores and subfactor scores as compared with nonpsychiatric controls, whereas bipolar patients had intermediate scores between both groups. Significant correlations emerged between cognitive checklist for mania total and subcomponent scores and the DAS (total, performance subfactor, and approval subfactor scales) for the bipolar, but not the unipolar or nonpsychiatric control groups. Core beliefs among bipolar patients appear negativistic during manic phases, potentially reflecting an overcompensation for depression. The findings support clinical approaches targeting depressive cognitions regardless of the presence of manic symptoms.     

Adaptive cognitive emotion regulation moderates the relationship between dysfunctional attitudes and depressive symptoms during a stressful life period: A prospective study

Background and objectivesDysfunctional cognitions are known to emerge in stressful situations and are critical for the onset of depressive symptoms. The goal of this study is to investigate whether adaptive and/or maladaptive emotion regulation strategies moderate the relationship between dysfunctional attitudes and depressive symptoms under stress.MethodsIn a longitudinal study, 92 healthy but unselected undergraduates were followed for three months including a stress period (four weeks of examinations).ResultsOur findings demonstrate that the more adaptive emotion regulation strategies are used in daily life (measured at baseline), the weaker the relationship between dysfunctional attitudes and depressive symptoms during stress. Interestingly, no single strategy demonstrates a unique predictive value, but only the combination of several adaptive strategies moderates the relationship between dysfunctional attitudes and depressive symptoms. Although participants with elevated depressive symptoms use more maladaptive emotion regulation strategies, these latter strategies do not moderate the association between dysfunctional attitudes and depressive symptoms.LimitationsThe use of a sample of undergraduates limits the generalizability and the clinical significance of our results.ConclusionsAltogether, although dysfunctional attitudes are activated and accessible in response to certain life stressors, the strategies that healthy individuals use to adaptively regulate these cognitions seem important in determining the likelihood of depressive symptoms.     

Cognitive change processes in a group cognitive behavior therapy of depression

The present study attempted to examine the causal relationships among changes in automatic thoughts, dysfunctional attitudes, and depressive symptoms in a 12-week group cognitive behavior therapy (GCBT) program for depression. In all, 35 depressed patients attending the GCBT program were monitored with the Automatic Thoughts Questionnaire, Dysfunctional Attitudes Scale, and Beck Depression Inventory at the pre-treatment, 4th and 8th sessions, and post-treatment. The results were as follows: (1). GCBT reduces negative cognitions; (2). changes in automatic thoughts and dysfunctional attitudes lead to change in depressive symptoms; and (3). automatic thoughts play a mediating role between dysfunctional attitudes and depression. The findings taken as a whole support the Causal Cognition Model of depression.     

Current evidence for aripiprazole as augmentation therapy in major depressive disorder

Aripiprazole (Abilify) is the first atypical antipsychotic approved as adjunctive therapy for the treatment of major depressive disorder. The pharmacological basis of the action of aripiprazole in major depressive disorder remains unclear, but it may be related to its potent partial agonism of the dopamine D(2)/D(3) receptors, partial agonism of the 5-hydroxytryptamine (5-HT)(1A) receptor and antagonism of the 5-HT(2A) receptor. This article reviews findings on the efficacy and tolerability of aripiprazole from two identical placebo-controlled trials and from smaller open-label and retrospective studies. At doses of 2-15 mg/day aripiprazole was efficacious and well tolerated as adjunctive therapy to antidepressants in patients who had not responded to monotherapy.     

Brain serotonin2 receptors in major depression: a positron emission tomography study

BACKGROUND: Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone). METHODS: Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis. RESULTS: There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels. CONCLUSION: This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.     

Imaging the serotonin transporter during major depressive disorder and antidepressant treatment

This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occupancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art method is [11C]DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography. [11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantitation of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or unblocked 5-HTT density in a medication-treated state. During major depressive episodes with no other axis I comorbidity, either no difference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake inhibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is approximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone. Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.     

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.     

Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS: Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS: The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS: These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.     

PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders

OBJECTIVE: To determine whether there are abnormalities in the in vivo status of the serotonin type 2A (5-HT2A) receptor in late-life depression and Alzheimer's disease, the authors used positron emission tomography (PET) to assess patients with these two conditions and healthy subjects. METHOD: PET was performed by using [18F]altanserin to evaluate 5-HT2A receptor binding in 11 elderly patients with depression (four men, seven women; mean age = 65.0 years, SD = 5.5); nine Alzheimer's disease patients, including three with concurrent depression (two men, seven women; mean age = 69.7 years, SD = 5.0); and 10 age-matched healthy subjects (four men, six women; mean age = 69.8 years, SD = 5.0). Partial-volume correction of regional specific binding estimates was performed by using a method based on magnetic resonance imaging. RESULTS: No significant abnormalities in [18F]altanserin binding (binding potential) were observed in the patients with late-life depression, and no effect of depression on binding potential was present within the Alzheimer's disease group. However, the patients with Alzheimer's disease had significantly lower binding than the normal subjects in several brain regions, including the anterior cingulate, prefrontal cortex, and sensorimotor cortex. CONCLUSIONS: These results suggest that the 5-HT2A receptor is differentially affected in late-life depression and Alzheimer's disease, a finding that has implications for the etiological basis of mood and cognitive features of neuropsychiatric disorders of late life.     

Prolactin and cortisol responses to d-fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function.

OBJECTIVE: Theoretically, d-fenfluramine should be a more selective serotonin (5-HT) challenge agent and has much greater clinical tolerance than the racemic compound that has previously been used. The authors' goal, therefore, was to look at 5-HT function in depression using the d isomer of fenfluramine as a probe. METHOD: They evaluated central 5-HT function in 23 patients with DSM-III-R-diagnosed major depression and 16 healthy control subjects. The depressed group included 10 men and 13 women; four were outpatients, two attended a day hospital facility, and 17 were inpatients. Subjects were cannulated at 8:30 a.m. after an overnight fast. After baseline samples were drawn, 30 mg of d-fenfluramine was administered orally and blood samples were drawn over the following 5-hour period for prolactin and cortisol estimation. RESULTS: The plasma prolactin responses of the depressed patients were significantly lower than those of the control subjects. This blunting was not related to the severity of the depression but was significantly related to the patients' levels of state anxiety. Cortisol responses as well as prolactin responses were impaired in depression. High baseline cortisol levels were correlated with the severity of depression and the presence of weight loss. CONCLUSIONS: Overall, these findings indicate that there is diminished 5-HT responsivity in the depressed state.