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Narwhals and belugas are toothed whales belonging to the Monodontidae. Belugas have a circumpolar Arctic and sub-Artic distribution while narwhals are restricted to the Atlantic Arctic. Their geographical ranges overlap during winter migrations in the Baffin Bay area (Canada/West Greenland) and successful interbreeding may occur. Here, we employed geometric morphometrics on museum specimens to explore the cranium and mandible morphology of a known hybrid (NHMD MCE 1356) and the cranium morphology of a putative hybrid (NHMD 1963.44.1.4) relative to skull morphological variation in the parental species. Specifically, we used 3D models of skulls from 69 belugas, 86 narwhals, and the two known/putative hybrids and 2D left hemi-mandibles from 20 belugas, 64 narwhals and the known hybrid. Skull shape analyses allowed clear discrimination between species. Narwhals are characterised by a relatively short rostrum and wide neurocranium while belugas show a more elongated and narrower cranium. Sexual size dimorphism was detected in narwhals, with males larger than females, but no sexual shape dimorphism was detected in either species (excluding presence/absence of tusks in narwhals). Morphological skull variation was also dependent on different allometric slopes between species and sexes in narwhals. Our analyses showed that the cranium of the known hybrid was phenotypically close to belugas but its 2D hemi-mandible had a narwhal shape and size morphology. Both cranium and mandible were strongly correlated, with the pattern of covariation being similar to belugas. The putative hybrid was a pure male narwhal with extruded teeth. Comparison of genomic DNA supported this result, and stable carbon and nitrogen isotope values suggested that the putative hybrid had a more benthic foraging strategy compared to narwhals. This work demonstrates that although the known hybrid could be discriminated from narwhals and belugas, detection of its affinities with these parental species was dependent on the part of the skull analysed.

Background Yoga interventions offer promise for the treatment of major depressive disorder (MDD), yet their safety and potential impact on suicidal ideation (SI) have not been well documented. This study evaluated the safety of a randomized controlled dose-finding trial of Iyengar yoga plus coherent breathing for individuals with MDD, as well as the potential effects of the intervention on SI without intent. Methods Participants with Beck Depression Inventory-II (BDI-II) scores ≥14 and a diagnosis of MDD (using DSM-IV criteria) were randomized to either a low dose group (LDG) or high dose group (HDG) and received a 12-week manualized intervention. The LDG included two 90-min yoga classes plus three 30-min homework sessions weekly. The HDG offered three 90-min classes plus four 30-min homework sessions weekly. Results Thirty-two individuals with MDD were randomized, of which 30 completed the protocol. At screening, SI without intent was endorsed on the BDI-II by 9 participants; after completing the intervention, 8 out of 9 reported resolution of SI. There were 17 adverse events possibly-related and 15 definitely-related to the intervention. The most common protocol-related adverse event was musculoskeletal pain, which resolved over the course of the study. Conclusions The Iyengar yoga plus coherent breathing intervention was associated with the resolution of SI in 8 out of 9 participants, with mild side effects that were primarily musculoskeletal in nature. This preliminary evidence suggests that this intervention may reduce SI without intent and be safe for use in those with MDD.

Objectives: The aims of this study were to assess the effects of an intervention of Iyengar yoga and coherent breathing at five breaths per minute on depressive symptoms and to determine optimal intervention yoga dosing for future studies in individuals with major depressive disorder (MDD). Methods: Subjects were randomized to the high-dose group (HDG) or low-dose group (LDG) for a 12-week intervention of three or two intervention classes per week, respectively. Eligible subjects were 18–64 years old with MDD, had baseline Beck Depression Inventory-II (BDI-II) scores ≥14, and were either on no antidepressant medications or on a stable dose of antidepressants for ≥3 months. The intervention included 90-min classes plus homework. Outcome measures were BDI-II scores and intervention compliance. Results: Fifteen HDG (Mage = 38.4 ± 15.1 years) and 15 LDG (Mage = 34.7 ± 10.4 years) subjects completed the intervention. BDI-II scores at screening and compliance did not differ between groups (p = 0.26). BDI-II scores declined significantly from screening (24.6 ± 1.7) to week 12 (6.0 ± 3.8) for the HDG (–18.6 ± 6.6; p 50% decrease in BDI-II scores; p = 0.65) for the HDG (13/15 subjects) and LDG (11/15 subjects) or remission (i.e., number of subjects with BDI-II scores

Objective: To determine if a 12-week yoga intervention (YI) was associated with increased gamma aminobutyric acid (GABA) levels and decreased depressive symptoms in participants with major depressive disorder (MDD). Methods: Subjects were randomized to a high-dose group (HDG) of three YIs a week and a low-dose group (LDG) of two YIs a week. Thalamic GABA levels were obtained using magnetic resonance spectroscopy at Scan-1 before randomization. After the assigned 12-week intervention, Scan-2 was obtained, immediately followed by a YI and Scan-3. Beck Depression Inventory II (BDI-II) scores were obtained before Scan-1 and Scan-3. Settings/Location: Screenings and interventions occurred at the Boston University Medical Center. Imaging occurred at McLean Hospital. Subjects: Subjects met criteria for MDD. Intervention: Ninety minutes of Iyengar yoga and coherent breathing at five breaths per minute plus homework. Outcome measures: GABA levels and the BDI-II. Results: BDI-II scores improved significantly in both groups. GABA levels from Scan-1 to Scan-3 and from Scan-2 to Scan-3 were significantly increased in the LDG (n = 15) and showed a trend in the total cohort. Post hoc, participants were divided into two groups based on having an increase in GABA levels at Scan-2. Increases in Scan-2 GABA levels were observed in participants whose mean time between their last YI and Scan-2 was 3.93 ± 2.92 standard deviation (SD) days, but not in those whose mean time between their last YI and Scan-2 was 7.83 ± 6.88 SD. Conclusions: This study tentatively supports the hypothesis that one of the mechanisms through which yoga improves mood is by increasing the activity of the GABA system. The observed increase in GABA levels following a YI that was no longer observed 8 days after a YI suggests that the associated increase in GABA after a YI is time limited such that at least one YI a week may be necessary to maintain the elevated GABA levels.

Evidence suggests that yoga may be an effective treatment for major depressive disorder (MDD). Studies evaluating the "dosing" of yoga treatment and efficacy for MDD are needed. The goal of this study was to assess the effects of an intervention combining Iyengar yoga and coherent breathing in participants with MDD and determine the optimal intervention dose.Thirty-two participants (18 to 65 y of age) diagnosed with MDD were randomized to a high-dose group (HDG) or a low-dose group (LDG) of yoga and coherent breathing for 12 weeks. The HDG (n=15) involved three 90-minute yoga classes and four 30-minute homework sessions per week. The LDG (n=15) involved two 90-minute yoga classes and three 30-minute homework sessions per week. Participants were evaluated at baseline, week 4, week 8, and week 12 with the following instruments: Positivity Self-Test, Spielberger State Anxiety Inventory, Patient Health Questionnaire-9, Pittsburgh Sleep Quality Index, and Exercise-induced Feeling Inventory. Data were analyzed using intent-to-treat methods.Significant improvements in all outcome measures were found for both groups, with acute and cumulative benefits. Although the HDG showed greater improvements on all scales, between-group differences did not reach significance, possibly due to lack of power because of the small sample size. Cumulative yoga minutes were correlated with improvement in outcome measures.This dosing study did not include a non-yoga control.Improvement in psychological symptoms correlated with cumulative yoga practice. Both interventions reduced symptoms of depression and anxiety and increased feelings of positivity. The time commitment for yoga practice needs to be weighed against benefits when designing yoga interventions.

Background This study evaluated the effects of the Breath-Body-Mind Workshop (BBMW) (breathing, movement, and meditation) on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease (IBD). Methods Twenty-nine IBD patients from the Jill Roberts IBD Center were randomized to BBMW or an educational seminar. Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory 18, IBD Questionnaire, Perceived Disability Scale, Perceived Stress Questionnaire, Digestive Disease Acceptance Questionnaire, Brief Illness Perception Questionnaire, fecal calprotectin, C-reactive protein, and physiological measures were obtained at baseline and weeks 6 and 26. Results The BBMW group significantly improved between baseline and week 6 on Brief Symptom Inventory 18 (P = 0.02), Beck Anxiety Inventory (P = 0.02), and IBD Questionnaire (P = 0.01) and between baseline and week 26 on Brief Symptom Inventory 18 (P = 0.04), Beck Anxiety Inventory (P = 0.03), Beck Depression Inventory (P = 0.01), IBD Questionnaire (P = 0.01), Perceived Disability Scale (P = 0.001), and Perceived Stress Questionnaire (P = 0.01) by paired t tests. No significant changes occurred in the educational seminar group at week 6 or 26. By week 26, median C-reactive protein values decreased significantly in the BBMW group (P = 0.01 by Wilcoxon signed-rank test) versus no significant change in the educational seminar group. Conclusions In patients with IBD, participation in the BBMW was associated with significant improvements in psychological and physical symptoms, quality of life, and C-reactive protein. Mind-body interventions, such as BBMW, which emphasize Voluntarily Regulated Breathing Practices, may have significant long-lasting benefits for IBD symptoms, anxiety, depression, quality of life, and inflammation. BBMW, a promising adjunctive treatment for IBD, warrants further study.

Serotonin abnormalities have been reported in the brain of suicide victims. Evidence of a serotonin deficiency in suicide attempters is less consistent. We hypothesized that a serotonin deficiency may be present in suicide attempters whose attempt behavior more closely approximates completed suicide.Sixty-seven (67) drug-free depressed inpatients (46 suicide attempters, 21 nonattempters) underwent research clinical assessments and a lumbar puncture. Cerebrospinal fluid (CSF) monoamine metabolites were assayed. Degree of medical damage and intent of the most recent suicide attempt were rated.CSF amine metabolites did not differentiate suicide attempters as a group from nonattempters. However, reduced serotonergic activity, as indicated by lower levels of CSF-5-hydroxyindoleacetic acid (5-HIAA) was associated with a history of planned suicide attempts and with suicide attempts that resulted in greater medical damage. Other monoamine metabolites did not correlate with seriousness of suicidal behavior, except for low CSF homovanillic acid and higher medical damage. No correlation was found with violent method.Planned and more medically damaging suicide attempts appear to be associated specifically with low serotonergic activity and, therefore, resemble completed suicide both behaviorally and biochemically. It remains to be determined whether low levels of CSF 5-HIAA can predict greater medical damage in future suicide attempts.

Previous research has suggested that major depression and suicidal behavior may be associated with altered serotonin receptor function. In this study, platelet serotonin2 (5-HT2) receptor binding indices were measured in conjunction with serotonin-amplified platelet aggregation, a response mediated by the platelet 5-HT2 receptor complex, in depressed patients and normal controls. The magnitude of serotonin-amplified platelet aggregation was positively correlated with the number of platelet 5-HT2 receptor sites in both groups. Mean values for the receptor binding indices and the receptor-mediated response did not differ significantly between patients and controls, although patients exhibited a wider range of values for each parameter compared with controls. Exploratory analyses were undertaken to determine clinical variables that might contribute to the increased variance in depressed individuals. These analyses failed to reveal a statistically significant relationship between any of the platelet 5-HT2 receptor measures and the subtype or severity of depressive illness, or the presence of comorbid borderline personality disorder. Although the mean number of receptor sites did not differ between patients who had recently attempted suicide and those who had never attempted suicide, a strong positive correlation (p = 0.002) was found between receptor number and the degree of medical damage resulting from the suicidal act. Furthermore, the ratio of the serotonin-amplified platelet aggregation response to platelet 5-HT2 receptor number, an index of the mean responsivity of an individual receptor complex, was lower in suicide attempters versus nonattempters (p = 0.06) and normal controls (p = 0.01). Exploratory analyses also suggested that recent exposure to psychotropic medication may result in a significant increase in platelet 5-HT2 receptor number (p = 0.03). Thus, although the study did not show a consistent alteration in platelet 5-HT2 receptor indices in major depression, the data suggest that specific factors such as suicidality and drug exposure may explain some of the variance in depressed patients.

Studies of suicide risk factors generally examine suicidal behavior as a dichotomous outcome. Survival analytic techniques are discussed in which the time until a suicide attempt from a specific point, such as prior attempt or onset of illness, is also examined. These procedures can incorporate information on those lost to followup or “censored.” One survival analytic technique, Cox's proportional hazards model, is a particularly informative statistical technique for the study of suicidal risk factors because several covariates can be incorporated. Illustrative analyses estimate the significance of different risk factors, and demonstrate that there is a 32% increase in the relative risk of a suicide attempt associated with each prior attempt.

Several processes have been described that could explain geographical variation and speciation within small islands, including fragmentation of populations through volcanic eruptions. Massive landslides, or debris avalanches, could cause similar effects. Here we analyse the potential impact of the 0.8 million-year-ago (Ma) Güimar valley debris avalanche on the phylogeography of the lizard Gallotia galloti on the Canary Island of Tenerife. Distributions of mitochondrial DNA lineages (based on cytochrome b sequences) were analysed on a 60-km southeastern coast transect centred on this area. Three main clades were detected, which can be divided into northern (one clade) and southern (two clades) groups that introgress across the valley. Maximum-likelihood estimates of migration rates (scaled for mutation rate) revealed highly asymmetric patterns, indicating that long-term gene flow into this region from both the northern and the southern populations greatly exceeded that in the opposite directions, consistent with recolonization of the area. The ancestral Tenerife node on the G. galloti tree is estimated at 0.80 Ma, matching closely with the geological estimate for the debris avalanche. Morphological variation (body dimensions and scalation) was also analysed and indicated a stepped cline in female scalation across the valley, although the patterns for male scalation and male and female body dimensions were not as clear. Together these findings provide support for the hypothesis that the debris avalanche has shaped the phylogeography of G. galloti and may even have been a primary cause of the within-island cladogenesis through population fragmentation and isolation. Current estimates of timing of island unification mean that the original hypothesis that within-island diversity is explained by the secondary contact of populations from the two ancient precursor islands of Teno and Anaga is less plausible for this and some other Tenerife species. Large-scale landslides have occurred on many volcanic islands, and so may have been instrumental in shaping within-island diversities.

We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.

Previous studies have demonstrated blunted beta-adrenergic responsivity in leukocytes from depressed patients. We sought to determine if this blunted cyclic adenosine monophosphate (AMP) response is specific for beta-adrenergic receptors (homologous), or whether other adenylyl cyclase-coupled receptors are also involved (heterologous), in order to localize this effect at the level of the receptor versus the coupling protein or the transducer, adenylyl cyclase. We studied adenylyl cyclase-mediated responses in peripheral blood mononuclear cells from 95 drug-free patients with a major depressive episode and 69 healthy controls. We found a similar degree of decrease in the peak cyclic AMP response to activation of the beta-adrenergic receptor (28%) and the prostaglandin receptor (34%) in the depressed patients, which indicated heterologous desensitization. Forskolin cyclic AMP responses were not blunted. Blunting of cyclic AMP responses to isoproterenol did not appear to correlate with levels of plasma norepinephrine and epinephrine or hypothalamic—pituitary—adrenocortical function. The absence of a decrease in the peak forskolin-generated cyclic AMP response, which involves direct activation of adenylyl cyclase, suggests an abnormality at the level of the coupling protein in these adenylyl-coupled receptors in depressed patients. Future studies need to determine whether this leukocyte signal transduction defect in depression also involves brain adenylyl cyclase-coupled receptors.

We measured regional cerebral blood flow with the xenon 133 inhalation technique in 41 patients with major depressive disorder and 40 matched, normal controls during an eyes-closed, resting condition. The depressed group had a marked reduction in global cortical blood flow. To examine topographic abnormalities, traditional multivariate analyses were applied, as well as a new scaled subprofile model developed to identify abnormal functional neural networks in clinical samples. Both approaches indicated that the depressed sample had an abnormality in topographic distribution of blood flow, in addition to the global deficit. The scaled subprofile model identified the topographic abnormality as being due to flow reduction in the depressed patients in selective frontal, central, superior temporal, and anterior parietal regions. This pattern may reflect dysfunction in the parallel distributed cortical network involving frontal and temporoparietal polymodal association areas. The extent of this topographic abnormality, as revealed by the scaled subprofile model, was associated with both patient age and severity of depressive symptoms.

Seizures remain among the most serious side effects of psychotropic drugs. The authors review the literature associating neuroleptic and antidepressant medications with seizures, discussing the relative “seizurogenicity” of different medications, risk factors for seizures, and drugs of choice for high-risk patients. Case histories are presented. Available evidence suggests that molindone, fluphenazine, and haloperidol are among the least seizurogenic neuroleptics and that doxepin, monoamine oxidase inhibitors, or electroconvulsive therapy may be safest in treating the depressed patient at risk for seizures.

To investigate the effect of treatment modality on length of hospital stay, the authors retrospectively studied 86 admissions of 74 patients with major depression. All 19 patients who received ECT recovered, in contrast to only 27 (49%) of 55 patients given tricyclic antidepressants or other medication. The 28 patients who had not responded to antidepressants recovered after treatment with ECT. Treatment modality had a highly significant effect on length of hospital stay: patients given ECT stayed a mean of 13 fewer days, saving more than $6,400 per patient at current rates. These findings of significant economic and therapeutic benefits in the use of ECT raise issues about treatment selection for depressed inpatients.

A saturable, stereospecific high affinity beta 2 adrenergic receptor was demonstrated on intact human peripheral blood lymphocytes using the ligand [125I]-iodocyanopindolol ([125I]ICYP). A method is described for parallel measurements of saturation binding isotherms and isoproterenol-cAMP responsiveness in split samples of intact lymphocytes isolated from 40 ml. of whole blood. A significant positive correlation between beta receptor density (Bmax) and the ratio of maximal isoproterenol-generated cAMP to basal levels was found in healthy subjects (r = 0.65, p less than 0.001). A significant positive correlation was found between age and the fold increase over basal cAMP levels induced by isoproterenol. Older females had a significantly higher fold increase in cAMP levels after isoproterenol than older males. These effects were largely accounted for by the lower basal levels of cAMP in older subjects. Beta receptor binding indices (Bmax and KD) did not differ between males and females, or change with aging. The effects of age and sex upon cAMP levels appear to be at least partly mediated by mechanisms independent of the beta receptor. The method, which describes a convenient assay for parallel measurement of beta receptor binding and cAMP levels in small blood samples, represents a useful model for studying human beta receptor function.

This retrospective study compared the treatment responses of 34 primary, unipolar depressives without psychotic features and 30 with psychotic features. Patients were diagnosed by Research Diagnostic Criteria and received trials of tricyclic antidepressants, antipsychotics, the combination of the two, electroconvulsive therapy, or placebo and psychotherapy. Only three of 18 psychotic patients vs. 17 of 23 nonpsychotic patients responded to antidepressants alone. Electroconvulsive therapy and the combination of antipsychotic and antidepressant medication gave better responses. These data suggest that major depressive disorder with psychotic features is best considered as a distinct subtype rather than a severe variant of major depression.

Twenty-two patients with recurrent affective disorders received 1-mg dexamethasone suppression tests (DSTs) during multiple hospitalizations. Interepisode consistency of DST results was found in 82% of the subjects, which supports the use of this test as a predictor of relapse.

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.

In order to examine the hypothesis that abnormal adrenocortical function is associated with suicidal behavior, morning and afternoon plasma cortisols and 1-mg dexamethasone suppression tests (DSTs) were performed in 65 patients with primary major depressive disorder. Patients with recent suicide attempts (within 28 days before DST) were compared to patients who had made past attempts and those who had never made suicide attempts with respect to age, gender, severity of depression, and plasma cortisol levels. Plasma cortisol levels did not differ significantly among the three groups. Nonsuppression on the DST was associated with presence of delusions, increasing age, and global severity of depression, but not with suicide attemps.

• Nine outpatients meeting research criteria for probable Alzheimer's disease who had psychosis or behavioral disturbance participated in a single-blind, placebo-controlled pilot study. Oral haloperidol in doses of 1 to 5 mg daily improved target symptoms, confirmed by doubleblind ratings of videotaped interviews. Patients could not be maintained on more than 4 mg of haloperidol daily due to the severity of extrapyramidal side effects. Modified Mini-Mental State scores worsened while taking haloperidol, with only partial recovery in the final 4-week placebo phase. Severe extrapyramidal side effects and decline in cognitive function may compromise the efficacy of commonly used doses of neuroleptic drugs in patients with Alzheimer's disease.

It has been suggested that there are altered levels of norepinephrine or other neurotransmitters at functionally important receptors in patients with depressive disorders. This hypothesis is difficult to study in the human central nervous system. However, noradrenergic function can be assessed indirectly with peripheral-blood lymphocytes used as a model of the beta-adrenergic receptor complex. We found that drug-free inpatients with endogenous depression had lower isoproterenol-stimulated cyclic AMP levels in intact lymphocytes than did healthy control subjects (3.9 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01). The density and affinity of beta-adrenergic receptors were similar in controls and depressed subjects (beta-receptor number, 5.4 +/- 0.7 and 5.3 +/- 0.8 fmol per 10(6) cells; binding affinity, 106 +/- 7.6 vs. 99.2 +/- 11.4 pM, respectively). When the depressed patients were subdivided by psychomotor manifestations, binding characteristics were indistinguishable among the subgroups. However, a significant reduction in beta-adrenergic responsiveness was observed in patients with psychomotor agitation, as compared with controls (2.6 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01), but not in patients with psychomotor retardation (5.8 +/- 1.1 pmol per 10(6) cells, P less than 0.05). Thus, the desensitization of beta-adrenergic receptors was correlated more closely with the severity of psychomotor agitation than with the overall severity of depression.

Monoamine oxidase (MAO) inhibitors are effective antidepressants whose use is limited because of unwanted side effects and the possibility of a tyramine-induced hypertensive crisis (cheese reaction). (-)-Deprenyl (the official nonproprietary name for this substance is selegiline), a selective MAO type B inhibitor, may be safer and have fewer side effects, but its antidepressant efficacy is uncertain. A double-blind placebo-controlled study was carried out in depressed outpatients who were treated with (-)-deprenyl in an MAO type B selective dose range and at a higher nonselective dose range. (-)-Deprenyl did not have a statistically significant antidepressant effect after three weeks of treatment at doses of 10 mg/d. However, after six weeks and at higher doses (averaging about 30 mg/d for the second three weeks), (-)-deprenyl was superior to placebo in antidepressant effect with a positive response rate of 50% vs 13.6% and with a 41% reduction in the Hamilton Depression Rating Scale mean score vs 10% in the placebo-treated group. No hypertensive crises were seen. The rate of occurrence of side effects with (-)-deprenyl was no greater than with placebo. It was concluded that (-)-deprenyl is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of nonselective MAO inhibitors.

Previous studies of peripheral blood mononuclear cells isolated from drug-free, hospitalized patients with endogenous major depression have demonstrated a diminished adenosine 3',5'-monophosphate (cyclic AMP) response to single concentrations of isoproterenol as compared with that obtained from normal control subjects. We now report results of isoproterenol dose-response studies that indicate lower basal levels of cyclic AMP as well as diminished cyclic AMP levels in response to isoproterenol stimulation at concentrations ranging from 10(-10) to 10(-5) mol/L in drug-free, hospitalized patients with endogenous depression. The major factor responsible for the diminished cyclic AMP production in the depressed patients was a loss of receptor sites capable of cyclic AMP production. Taken together with our previously reported finding that beta-adrenergic antagonist binding was normal in peripheral blood mononuclear cells obtained from depressed patients, the results of the dose-response studies suggest a loss of receptor function (desensitization) rather than a diminished number of receptor binding sites (down-regulation) as the underlying mechanism. Potential explanations for beta-adrenergic desensitization and its implications for the catecholamine hypothesis of depressive disorders are discussed.