Depressed patients have higher body temperature: 5-HT transporter long promoter region effects.

BACKGROUND: Depression has been associated with a decrease in intracellular serotonin (5-HT) reuptake through its transporter, SERT. The 5-HT transporter long promoter region (5-HTTLPR) deletion in the SERT gene has also been associated with a decrease in 5-HT reuptake. Conversely, increases in extracellular 5-HT have been associated with increased temperature. It has not been established, however, whether body temperature in depressed patients is different from controls. Here, we hypothesized that temperature would be increased in depressed patients as well as in those with the 5-HTTLPR deletion. METHODS: A strict oral temperature protocol employed single, cross-sectional, naturalistic time-of-day temperature measures in 125 subjects (46 normal controls, 79 outpatients with major depression). Controls and depressed patients were free of psychotropic medication and classified by the Structured Clinical Interview for Psychiatric Diagnoses. Eighty-one of the subjects (68 depressed, 13 normal) were additionally genotyped for 5-HTTLPR polymorphisms. RESULTS: Depressed patients had a significantly higher uncorrected body temperature (mean +/- SD 98.38 +/- 0.61 degrees F) than controls (mean +/- SD 98.13 +/- 0.59 degrees F; F = 4.8, p = 0.03). An age (F = 14.09, p < 0.001) and time-of-day (11.4, p = 0.001) correction revealed a more robust (F = 14.02, p < 0.001) difference between depressed patients (mean +/- SD 98.44 +/- 0.55 degrees F) and controls (mean +/- SD 98.02 +/- 0.56 degrees F). When normalized for age and circadian differences between subjects, random, outpatient oral temperatures had a sensitivity of 63% and a specificity of 76% in identifying the depressed subjects from the controls. Independent of depression, subjects with the 5-HTTLPR deletion (short SERT allele) were warmer (mean +/- SD 98.33 +/- 0.65 degrees F) than those lacking the short allele on either chromosome (mean +/- SD 97.91 +/- 0.69 degrees F; F = 7.0, p = 0.01). However, the genotype did not explain the temperature differences between controls and depressed patients. CONCLUSION: This is the first demonstration of an increased daytime body temperature in cases with major depression. Subjects with a corrected temperature above 98.3 degrees F were 2.6-fold more likely to be depressed. The results may strengthen the hypothesis of an inflammatory component of depression. In addition, the findings suggest a potential link between genetic differences in 5-HT transport and body temperature.

Antidepressant effects on kinase gene expression patterns in rat brain.

Multiple kinase pathways determine serotonin transporter (SERT) regulation. We hypothesized a decrease in kinase expression with chronic selective serotonin reuptake inhibitor (SSRI) administration necessary to regulate extracellular serotonin. We studied whole brain kinase mRNA expression on Affymetrix gene chips in rats treated with placebo 3 and 21 days, fluoxetine 3 and 21 days, and citalopram 21 days. Protein kinase C (PKC)-delta, PKC-gamma, stress-activated protein kinase, cAMP-dependent protein kinase beta isoform, Janus protein kinase, and phosphofructokinase M were all down regulated chronically with citalopram and fluoxetine, but not with acute fluoxetine. The results are consistent with homeostasis of SERT function through a decrease in PK expression.

Fluvoxamine treatment of mixed anxiety and depression: evidence for serotonergically mediated anxiolysis.

Although increasing evidence suggests that selective serotonin reuptake inhibitor (SSRI) treatment may be effective for anxiety in addition to depression, SSRI anxiolysis has not been definitively related to the inhibition of serotonin (5-HT) transport. The gene that encodes for the human serotonin transporter (5-HTT) expresses its protein in neurons and in blood platelets, and both tissues respond to transport inhibition similarly in response to SSRI treatment. This study examined the relationship between the change in the 5-HTT's apparent affinity for 5-HT and the anxiolytic response in a group of 18 fluvoxamine-treated patients meeting Structured Clinical Interview for DSM-IV criteria for both generalized anxiety disorder and major depression. Significant decreases were found in both Hamilton anxiety and Hamilton depression scores over a 2-month treatment period. Robust increases were found in the apparent affinity constant (Km) for platelet 5-HT transport with treatment, and the increases covaried significantly with the decrease in anxiety (F = 4.97, p < 0.03). The pretreatment 5-HTT Km significantly correlated with the improvement in depression scores (r = 0.53, p < 0.03), consistent with the Hypothesis of Initial Conditions. These results suggest that the therapeutic effect of SSRI treatment can be linked to the magnitude and time-course of 5-HT transport inhibition effected with fluvoxamine, a drug that seems to have an antianxiety effect of the same magnitude as its effect on depression.

Serotonin reuptake is less efficient in taste aversion resistant than in taste aversion-prone rats.

We have previously reported the development of rat lines bred selectively for differences in taste aversion conditionability. Earlier studies demonstrated that the taste aversion resistant (TAR) animals exhibited lower concentrations of brain serotonin and consumed greater amounts of ethanol than their taste aversion prone (TAP) counterparts. In the present study, TAR rats demonstrated significantly less efficient brain serotonin transport compared to TAP rats, but the rat lines demonstrated similar levels of serotonin transporter or V(max) and similar whole brain paroxetine (a specific serotonin reuptake inhibitor) binding (B(max)). These results suggest that the rat lines differ in the mechanisms that transport serotonin into nerve endings, but do not differ in the binding of serotonin to the transporter or in the number of serotonin transport sites. The data support the hypothesis that genetically determined differences in the serotonin system contribute to individual differences in taste aversion conditionability. The findings further suggest that differences in serotonin transport may influence the propensity to self-administer ethanol.

Treatment of premenstrual mood symptoms.

For the sake of improvement in therapeutic approaches for women with cyclical menstrual symptoms, the presentation of premenstrual mood disturbances per se deserves specific consideration. Treatments studies for premenstrual mood symptoms have included conservative, supportive, nutritional, psychotropic, hormonal, and anovulatory measures. An analysis of the literature on premenstrual mood symptoms suggests that a rational schemata for diagnosis can yield a hierarchy of selected individualized treatments based on minimizing the intervention necessary for effective relief.

Diagnostic and treatment results from a southeastern academic center-based premenstrual syndrome clinic: the first year.

OBJECTIVES: We attempted to ascertain the following: (1) the yield of a structured workup in a premenstrual syndrome clinic coordinated by a university-based gynecology department in the southeast, (2) referral patterns and care provided before consultation, and (3) therapeutic outcomes. STUDY DESIGN: The first 100 women seen prospectively entered a uniform diagnostic and treatment protocol. Data analysis was performed with analysis of variance and confidence interval for a population proportion. RESULTS: Thirty-eight women (95% confidence interval 28% to 48%) had premenstrual syndrome, 24 had premenstrual magnification syndrome (95% confidence interval 16% to 32%), 13 had an affective or other psychiatric disorder (95% confidence interval 6% to 20%). Only 44% of women previously given a diagnosis of premenstrual syndrome were found to have premenstrual syndrome. Overall, 84% of women with premenstrual syndrome and premenstrual magnification syndrome responded to treatment. CONCLUSIONS: Too many women are still given the diagnosis of premenstrual syndrome without appropriate prospective documentation. Premenstrual magnification represents an important diagnostic category. Therapeutic responses to present treatments are encouraging.

Downregulation of serotonin receptor subtypes by nortriptyline and adinazolam in major depressive disorder: neuroendocrine and platelet markers.

Neuroendocrine and platelet markers of serotonin (5-hydroxytryptamine, 5-HT) receptor functioning are useful tools for studying the downregulation of 5-HT receptors, a leading hypothesis for the mechanism of action of antidepressant drugs. The 5-HT releaser fenfluramine raises body temperature as well as plasma concentrations of ACTH, cortisol, and prolactin. Pretreatment with the 5-HT1 antagonist pindolol did not block the hyperthermic response to fenfluramine, mediating its actions via non-5-HT1 receptor subtypes (presumably 5-HT2/1C). We observed blunted hyperthermic responses to fenfluramine in unmedicated patients with major depressive disorder. We also observed that the neuroendocrine responses to fenfluramine were decreased by chronic treatment with the tricyclic antidepressant nortriptyline but not by chronic treatment with tricyclic antidepressant nortriptyline but not by chronic treatment with adinazolam, a triazolobenzodiazepine with purported antidepressant activity. IC50 values for ketanserin inhibition of 5-HT-induced platelet shape change response, a marker of 5-HT2/1c receptors, were elevated after nortriptyline treatment in depressed patients, and this increase could be accounted for by those subjects who responded well to antidepressant treatment. Adinazolam treatment did not alter the platelet shape change response. Our data suggest that downregulation of 5-HT2/1c receptors may be linked to the clinical response of depressed patients treated with nortriptyline.

Kinetic effects of desmethylimipramine treatment on platelet serotonin uptake in depressed patients: a comparison with imipramine.

The kinetic effects of desmethylimipramine (DMI) on platelet serotonin (5HT) uptake were compared to those of imipramine (IMI) in eight DMI-treated depressed patients and seven IMI-treated depressed patients, and compared to values after patients were off drug for 19 (+/- 8 SD) and 33 (+/- 15) days. As expected, IMI was a stronger inhibitor of 5HT uptake than DMI during treatment, with the mean apparent Km in treated patients being elevated nearly threefold over that of the drug-free condition. In DMI-treated patients, the mean Km was elevated nearly twofold over that of the drug-free condition. Although DMI is considered a preferential norepinephrine uptake inhibitor, the results suggest the following: (1) Significant decreases in the apparent platelet 5HT affinity are achieved with DMI; (2) the inhibition kinetics in depressed patients are competitive; (3) there was a significant relationship between Km change and depression outcome with DMI discontinuation; and (4) DMI, as a metabolite, appears to contribute to the 5HT uptake inhibition of IMI in vivo.

Platelet serotonin uptake in men with family histories of alcoholism.

Platelet serotonin uptake kinetics were examined in a carefully screened group of 28 male subjects, half of whom had an alcoholic father. Paired subjects were matched for a variety of characteristics, including age, race, sex, substance use history, height/weight ratio, season, and time of day for platelet serotonin uptake assays. The family history positive group had a significantly (p = 0.01) higher mean Vmax for platelet serotonin uptake (64.1 +/- 19, SD) compared to the control group without family histories of first-degree relatives with alcoholism (53.8 +/- 19). No significant differences in the affinity constant (Km) or in the Hill constant were found between groups. The results are consistent with the possibility that a higher Vmax of platelet serotonin uptake indicates a biologic factor associated with alcoholism risk.

Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD.

One of the diagnostic criteria for posttraumatic stress disorder (PTSD) is an exaggerated startle response; however, this phenomenon has not been verified empirically. The authors compared 20 Vietnam combat veterans with PTSD and 18 combat veterans without PTSD on the eyeblink reflex electromyographic response of the startle reaction. Subjects in both groups who failed to show an eyeblink response to the startle stimuli were eliminated from further analyses. Among the remaining subjects, the 13 with PTSD had a significantly greater startle response amplitude than the 12 control subjects at intermediate intensities of acoustic stimuli. The relationship between startle responsivity and both negative and positive symptoms was also investigated.

Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients.

The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirone's effects on cortisol may occur after chronic gepirone administration.

Influence of negative affect on smoking cessation treatment outcome: a pilot study.

In order to determine whether baseline depression was related to initial success or failure in smoking cessation, we prospectively examined mood self-ratings in a pilot study of 43 unselected smokers attempting to quit smoking in an outpatient program. Mean pretreatment POMS depression scores in the subjects who were unable to quit were significantly higher compared to those successful in initially relinquishing smoking. These preliminary results suggest that a negative-affect group at high risk for failure in nicotine dependence treatment might be identified in advance by an assessment of mood done prior to treatment.

Gepirone as a 5-HT1A agonist in the treatment of major depression.

Twenty-four patients with major depression were treated in a single-blind design with 25 mg to 75 mg gepirone, a pyrimidinyl piperidinedione analog of buspirone with serotonin1A (5-HT1A) receptor affinity properties. Twenty-four-Item Hamilton Rating Scale for Depression-(HAM-D) scores decreased by 36 percent when mean baseline scores were compared with an endpoint analysis of 6 weeks' gepirone treatment. Several subjects demonstrated marked improvements over baseline. The data are discussed within the context of 5-HT1A receptor desensitization as a potential component of antidepressant treatment.

Effect of nicotine on human blood platelet serotonin uptake and efflux.

1. Physostigmine administration has been previously shown to decrease the uptake of serotonin in human platelets. In order to test whether uptake could be inhibited as a nicotinic-cholinergic effect, the in vitro effects of nicotine on platelet 5HT uptake and efflux were examined. 2. Nicotine stimulated release of serotonin from human blood platelets, and competitively inhibited human platelet serotonin uptake in a concentration-dependent fashion at in vitro concentrations as low as 20 microM for uptake. 3. The kinetics of the nicotine effects on uptake were different from those of physostigmine. Unlike the effects of physostigmine, nicotine produced different kinetic changes, with an increase in Km and no consistent change in Vmax. 4. The efflux and inhibition of uptake paralleled that previously reported in rat brain in vitro, and was likewise similar to concentrations found previously to augment extracellular amine in other tissue preparations. However, the effects of nicotine in human platelets were not reversible by nicotinic antagonism with hexamethonium. 5. The results distinguish human platelet from rat brain with respect to nicotinic antagonism, and suggest that, at similar concentrations, nicotine may increase extracellular serotonin through differing mechanisms.

Atenolol treatment of late luteal phase dysphoric disorder.

Activation of the renin-angiotensin-aldosterone system has been hypothesized as a potential pathophysiological factor in premenstrual tension syndrome (PMS). Atenolol is a predominate beta 1-blocker which can decrease plasma renin activity and inhibit the urinary excretion of aldosterone. Sixteen women meeting provisional diagnoses of late luteal phase dysphoric disorder were treated for symptoms of PMS with atenolol (50 mg once daily) in a randomized placebo-crossover double-blind design. The data indicated significant improvements on the irritability, vigor, elation, and friendliness scores in response to atenolol compared to placebo. Significant changes were not found for several other ratings scales, indicating that atenolol improved only selected symptoms in the group as a whole. However, the women who had premenstrual tension symptoms for more than 5 years (n = 8) were improved on most of the rating scales. Atenolol decreased premenstrual plasma aldosterone to a limited extent. There was also a trend in the data toward higher luteal progesterone levels during the month subjects took atenolol. Plasma renin activity and aldosterone correlated with estrogen and progesterone levels during the placebo month but not during the active month.

Platelet serotonin transport after a single ECT.

Platelet 5-HT uptake was examined in six depressed patients before and after a single electroconvulsive treatment and compared with six age- and sex-matched controls. The depressed patients had a significantly (P less than 0.05) lower Vmax of platelet 5-HT uptake prior to ECT (22.9 +/- 7.6 pm/2 x 10 platelets) than did control subjects (37.5 +/- 9.1 SEM). After a single ECT treatment, the Vmax significantly (P less than 0.05) increased to levels (34.6 +/- 10.1)no longer significantly different from control. The results are compared with recent data from depressed patients indicating that low baseline levels of platelet imipramine binding increase after ECT treatment.