Sex differences in diencephalon serotonin transporter availability in major depression.

BACKGROUND: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences. METHODS: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([(123)I]beta-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [(123)I]beta-CIT (225.7 +/- 3.7 MBq) and imaged 23.0 +/- 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression. RESULTS: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [(123)I]beta-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [(123)I]beta-CIT uptake in depressed women compared with less than a 1% decrease in depressed men. CONCLUSIONS: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants.

Beyond monoamines: glutamatergic function in mood disorders.

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

Lack of association between suicidal ideation and enhanced platelet 5-HT2A receptor-mediated calcium mobilization in cancer patients with depression.

BACKGROUND: Increased density of 5-HT2A receptors was observed in the platelets of depressive patients with suicidal ideation. Enhanced 5-HT2A receptor-mediated platelet calcium mobilization has been proposed as a biological marker for the pathophysiology of major depression in cancer patients as well as in physically healthy patients. To examine whether depressive cancer patients with suicidal ideation have enhanced 5-HT2A receptor-mediated platelet response compared with those without suicidal ideation, we compared 5-HT-induced platelet calcium mobilization in depressive cancer patients with and without suicidal ideation. METHODS: 5-HT-induced platelet calcium mobilization was examined in 24 cancer patients diagnosed as having major depression according to the DSM-IV criteria. Suicidal ideation was evaluated by the Hamilton Depression Rating Scale and Zung's Self Depression Scale, as well as by the DSM-IV criteria. RESULTS: There was no significant differences in 5-HT-induced platelet calcium response between the depressive cancer patients with (n = 8) and without suicidal ideation (n = 16). 5-HT-induced platelet calcium response was also not significantly associated with the severity of suicidal ideation or with the severity of depression assessed by Hamilton Depression Rating Scale and Zung's Self Depression Scale. CONCLUSIONS: These findings suggest that enhanced 5-HT2A receptor-mediated response was not associated with suicidal ideation in cancer patients with depression.

Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors.

BACKGROUND: Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations. METHODS: Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment). RESULTS: In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response. CONCLUSIONS: Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.

Central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder.

BACKGROUND: A previous single photon emission computed tomography study showed decreased central type benzodiazepine receptors in the prefrontal cortex in Vietnam War veterans with posttraumatic stress disorder. To assess the generalizability of this finding to patients with more recent history, we studied central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder. METHODS: Nineteen Gulf War veterans with posttraumatic stress disorder and 19 age-matched, healthy, nondeployed veterans participated in a single photon emission computed tomography study using [(123)I]iomazenil. Regional total distribution volume (V(T)') was compared between two groups using Statistical Parametric Mapping 99 (Wellcome Department of Imaging Neuroscience, London, United Kingdom) and volumes of interest analysis. RESULTS: Benzodiazepine receptor levels did not show regional differences between the two groups, either with or without global normalization. Average difference in V(T)' was 2% across brain areas; however, by applying global normalization, V(T)' in the patient group showed significant negative correlation with childhood trauma scores in the right superior temporal gyrus. CONCLUSIONS: Less severe symptoms and shorter duration of the illness in the current group than the prior one may be the source of the difference in the results of the two studies.

Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT.

BACKGROUND: A recent magnetic resonance spectroscopy (MRS) study revealed low gamma-aminobutyric acid (GABA) levels in the occipital cortex of depressed patients. No in vivo study has been reported to measure postsynaptic GABA receptors in the patients. METHODS: Cortical benzodiazepine (BZ) binding to GABA(A) receptors was measured with [(123)I]iomazenil and single photon emission computed tomography in unmedicated patients with unipolar major depression (n = 13) and healthy subjects (n = 19). Group differences were evaluated by means of statistical parametric mapping (SPM) with partial volume correction for gray matter. Occipital GABA levels were determined by proton MRS in a subgroup (n = 6) of the patients. RESULTS: No evidence of altered BZ binding was found in patients with depression compared with healthy control subjects in the SPM analysis. Although reduction in gray matter volume was observed in the frontal cortex and amygdala of the patients, partial volume correction of the atrophy did not change the result of unaltered BZ binding. GABA levels were found lower in the occipital cortex; however, BZ binding did not show significant relationship to GABA levels. CONCLUSIONS: GABA(A) receptor binding measured in vivo with BZ radioligand binding are not altered in patients with depression.

Relationship between distressing cancer-related recollections and hippocampal volume in cancer survivors.

OBJECTIVE: Having cancer is extremely stressful, and distressing cancer-related recollections are frequently reported by cancer survivors. Smaller hippocampal volume has been observed in stress-related neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and major depression. The aim of this study was to determine whether there is a similar association between distressing cancer-related recollections and hippocampal volume. METHOD: The subjects were 67 women who had had breast cancer surgery 3 or more years earlier and had no history of PTSD or major depression before the cancer. Each woman was evaluated with a semistructured interview to determine whether she had a history of distressing cancer-related recollections. Hippocampal volume was measured by three-dimensional magnetic resonance imaging, and memory function was assessed by the Wechsler Memory Scale-Revised. RESULTS: The volume of the left hippocampus was significantly smaller (5%) in the subjects with a history of distressing cancer-related recollections (N=28) than in those without any such history (N=39). There was no significant difference in right hippocampal volume or whole brain volume measured as a control. There were no significant differences in delayed memory or percentage retention. However, significantly worse immediate visual memory, but not verbal memory, was observed in the subjects with a history of distressing cancer-related recollections. CONCLUSIONS: Having distressing cancer-related recollections is associated with smaller left hippocampal volume in survivors of breast cancer.

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.

Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response.

Electrophysiological studies suggest that alpha2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic firing rates. Recent reports suggest that alpha2-antagonism may hasten and improve the response to antidepressant medications. To test this hypothesis, a randomized double-blind controlled trial was undertaken to determine if the combination of an alpha2-antagonist (yohimbine) with a selective serotonin reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of major depressive disorder confirmed by SCID interview were randomly assigned to receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose of yohimbine (F/Y). The yohimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preserving manner. Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6 weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group using both the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (chi2(1) = 5.86, p = 0.016 and chi2(1) = 5.29, p = 0.021, respectively). At the last observed visit, 18 (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10 (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs 10 (42%) of 24 F/P subjects were responders. The addition of the alpha2-antagonist yohimbine to fluoxetine appears to hasten the antidepressant response. There is also a trend suggesting an increased percentage of responders to the combined treatment at the end of the 6-week trial.

Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration.

Few studies have demonstrated in vivo alterations of human serotonin and dopamine transporters (SERTS and DATS) during antidepressant treatment. The current study measured these transporter availabilities with [(123)I]beta-CIT single photon emission computed tomography (SPECT) during administration of selective serotonin reuptake inhibitors (SSRIs) or a non-SSRI, bupropion. A total of 17 healthy human subjects were randomly assigned to two different treatment protocols: (1). citalopram (40 mg/day) followed by augmentation with bupropion (100 mg/day) or (2). bupropion (100-200 mg/day) for 16 days. Citalopram significantly inhibited [(123)I]beta-CIT binding to SERT in brainstem (51.4%) and diencephalon (39.4%) after 8 days of administration, which was similarly observed after 16 days. In contrast, citalopram significantly increased striatal DAT binding by 15-17% after 8 and 16 days of administration. Bupropion and its augmentation to citalopram did not have a significant effect on DAT or SERT. In 10 depressed patients who were treated with paroxetine (20 mg/day), a similar increase in DAT and inhibition of SERT were observed during 6 weeks treatment. The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction.