The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence.

OBJECTIVE: The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders. METHOD: The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category. RESULTS: Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size=-0.01, 95% CI=-0.36 to 0.34). CONCLUSIONS: Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders.

The relationship between psychiatry residency applicant evaluations and subsequent residency performance.

OBJECTIVE: The goal of this study was to measure the predictive value of applicant evaluations for a psychiatry residency in terms of the subsequent performance of those who matriculated in the program. METHOD: The match lists for resident cohorts beginning their course of training over 4 years were divided into thirds, which served as our primary, preresidency measure of expected performance. The preresidency applicant evaluations of those residents who entered were compared to their postresidency evaluations. RESULTS: There was no significant association between preresidency selection evaluations and postresidency final evaluations in any of the four cohorts of trainees. CONCLUSIONS: The overall results of this study of four cohorts of residents indicate only a small, nonsignificant association between pre- and postresidency evaluations. Further efforts to predict residency performance in applicants may help identify those trainees who might benefit from additional monitoring and supervision.

Effect of stress on pregnancy outcome among women undergoing assisted reproduction procedures.

BACKGROUND: This study was performed to examine the effect of stress on pregnancy outcome in women who underwent assisted reproductive technology (ART) procedures. METHODS: In a controlled clinical study of healthy volunteers in an academic research environment, stress was measured subjectively by administering patient questionnaires and biochemically by examining urinary excretion of cortisol and 6-sulfatoxy-melatonin (6-SM), the primary metabolite of melatonin and a marker of peripheral stress response. A total of 42 women who underwent ART procedures during an 18-month period agreed to participate in the study and were enrolled consecutively. The women collected 24-hour urine specimens on the day after human chorionic gonadotropin administration and concurrently completed the State-Trait Anxiety Inventory questionnaire. We measured the cortisol and 6-SM levels in the urine collection for each of the 42 women and for 10 oocyte donors who served as controls. Pregnancy tests were performed 14 days after embryo transfer. Analysis of covariance was used to compare the relationship of stress ratings to urinary cortisol and 6-SM levels among the women who became pregnant, the women who did not, and the women who served as controls. Other variables were explored by performing chi2 analysis and Fisher's exact test. RESULTS: Neither self-ratings of acute anxiety, nor total daily 6-SM value, nor cortisol levels were associated with pregnancy outcome in the ART procedures. CONCLUSION: Biochemical markers of stress failed to support a deleterious effect of stress on pregnancy outcome in women who underwent ART procedures. Subjective measurement of stress levels did not differ between women who became pregnant and those who did not.

The effects of mirtazapine on plasma lipid profiles in healthy subjects.

BACKGROUND: The novel antidepressant mirtazapine has been linked to elevated random plasma total cholesterol (TC) levels. The purpose of this study was to evaluate in a more controlled and precise approach the putative effects of mirtazapine on plasma lipids. METHOD: In a double-blind design, 50 healthy subjects (30 women and 20 men) were randomized to receive either mirtazapine (N = 28) or placebo (N = 22) for a 4-week period. The study was conducted from June 1997 to September 1998. The initial dose for the mirtazapine group was 15 mg daily, which was increased to 30 mg daily at the beginning of the second week. Body weight and plasma lipoprotein profiles, including TC, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides, were determined at baseline and at weekly intervals throughout the study period. RESULTS: At baseline, there were no group differences in any of the measures. There was a statistically significant increase of 2.5% in mean body weight over the course of the study in the mirtazapine group that appeared to reach a plateau at 3 weeks, while no increase was observed in the placebo group. Mirtazapine subjects also showed significantly increased TC at week 4 (p =.016) and a transient rise in triglycerides that normalized by week 4. No significant changes in any of the other lipid parameters, including HDL, LDL, and TC/HDL ratios, were observed within either group. Changes in TC were significantly and positively correlated with changes in weight (p <.01). CONCLUSION: These results suggest that while mirtazapine may be associated with increased TC, it does not increase LDL levels or affect the ratio of TC to HDL.

A longitudinal study of serotonergic function in depression.

Several reports have described abnormal neuroendocrine responses to serotonergic challenge tests in depression, but few have studied depressed patients followed longitudinally. In order to determine whether blunted prolactin responses to clomipramine challenge is a "state" vs. "trait" marker in depression, we applied this challenge paradigm to 20 patients with Major Depression prior to treatment and at three additional time points following response to desipramine: at the completion of acute treatment; at the end of the continuation phase of treatment; and after a minimum of three weeks "washout" following the discontinuation of treatment. The prolactin response to clomipramine challenge was blunted in depressed patients compared with matched healthy control subjects, at each time point over the longitudinal course of their illness and recovery. Challenge test results in depressed patients did not change after response to acute desipramine therapy, at the conclusion of the continuation phase of treatment, or while in a medication-free state of remission. Blunted prolactin response to clomipramine challenge persists in depressed patients after recovery from acute illness, and may reflect an underlying biological vulnerability.

Noradrenergic function and clinical outcome in antidepressant pharmacotherapy.

Controversy remains regarding the role of noradrenergic systems in determining clinical response to antidepressant pharmacotherapy. Pineal gland production of melatonin can serve as a physiologic index of noradrenergic function. The aim of this study was to examine the effects of antidepressant treatment on 24-hour urinary excretion of the principle metabolite of melatonin, 6-sulfatoxymelatonin in treatment responders and nonresponders. Twenty-four outpatients meeting DSM-III-R criteria for Major Depression received treatment with either fluvoxamine or imipramine for 6 weeks while participating in a placebo-controlled double-blind clinical trial. Twenty-four hour excretion of 6-sulfatoxymelatonin was measured at baseline and at the conclusion of the treatment trial. Changes in urinary excretion of 6-sulfatoxymelatonin distinguished antidepressant responders from nonresponders, with a significant increase observed in the former group and a significant decrease in the latter. The degree of clinical response was correlated with the change in 6-sulfatoxymelatonin excretion. These results suggest that enhanced noradrenergic function may play an important role in determining clinical response to antidepressant pharmacotherapy.

Ethnicity and seizure threshold.

1. Seizure threshold is an important variable in modern ECT treatment planning. To date, age, gender, and electrode placement have been used to predict seizure threshold, but the potential impact of ethnicity has received little attention. 2. In a retrospective pilot study of patients who received ECT, 20 pairs of first admission, right unilateral-treated, age- and sex-matched black and white patients were compared. 3. Black patients had higher seizure thresholds and were more likely to require restimulation, despite the finding that they were more likely to have been receiving concomitant medications which lower seizure threshold. However, ethnicity was confounded with variations in ECT dose titration, which were the strongest predictor of seizure threshold. 4. There were no differences in seizure length. Further study is necessary to confirm the impact of ethnicity on seizure threshold.

Psychobiological markers of stress in pregnancy: 6-sulfatoxymelatonin--a longitudinal study.

Maternal stress, physical and psychological, has been associated with adverse pregnancy outcome. The pineal gland is a physiological transducer that reflects adrenergic input. In a recent pilot study, we found urinary 6-sulfatoxymelatonin, the melatonin metabolite, to be elevated after a women spent a day at work compared to levels after a day off work, a leisure day. To evaluate the value of melatonin as a marker of stress, we evaluate melatonin metabolite levels in 121 women, along with perceived anxiety levels and urinary cortisol. Urinary cortisol and maternal anxiety levels each were significantly higher after a work day compared to a leisure day p = .03 and p = .001, respectively. 6-Sulfatoxymelatonin was not significantly different between work and leisure. Changes in cortisol levels were correlated with changes in melatonin metabolite levels (r = .62, p = .001). There was no correlation between changes in anxiety between work and leisure and changes in 6-sulfastoxymelatonin. We found no correlation with 28 week 6-sulfatoxymelatonin or 28-week cortisol and birth weight or gestational age at delivery. Results of this study suggest that melatonin secretion may not be a valuable marker for stress in pregnancy.

The effects of serotonin3 receptor blockade on the psychobiological response to intravenous clomipramine in healthy human subjects.

BACKGROUND: The purpose of this study was to determine the role that serotonin (5-HT)3 receptors play in the prolactin and nausea responses to clomipramine challenge. METHODS: Twenty healthy subjects were randomly assigned to pretreatment with either the selective 5-HT3 receptor antagonist ondansetron, or placebo, prior to intravenous infusion with clomipramine. RESULTS: Ondansetron pretreatment had no effect on the prolactin response to clomipramine challenge. There was a trend toward decreased nausea with ondansetron pre-treatment. CONCLUSIONS: These findings are consistent with other data suggesting that 5-HT3 receptors do not play a major role in the prolactin response to 5-HT challenge in human subjects, but may mediate nausea associated with enhanced 5-HT neurotransmission.

Presurgical finite element analysis from routine computed tomography studies for craniofacial distraction: II. An engineering prediction model for gradual correction of asymmetric skull deformities.

Finite element analysis from routine computed tomography studies (CT/FEA) allows clinicians to predict the mechanical and anatomic consequences of specific distraction systems before human application. A realistic three-dimensional CT/FEA engineering model of an actual plagiocephalic infant with unicoronal synostosis was developed using 4215 parabolic triangular shell elements and intracranial pressure conditions ranging from 10 to 20 mmHg. The completed finite element analysis model was used to predict the anatomic outcome of multiaxial distraction delivered by hypothetical patterns of rod and node distraction units. The predictions for the various patterns of distraction units were also compared quantitatively with respect to force, stress, strain, and intracranial volume. Best anatomic corrections were achieved with bilateral patterns of distraction units that simultaneously elongated the ipsilateral cranium and shortened the contralateral cranium. Greatest strain levels were experienced within the osteotomy callus, greatest stress levels at the appliance anchorage sites, and the greatest rod force at the ipsilateral lower coronal position.

Pre-surgical CT/FEA for craniofacial distraction: I. Methodology, development, and validation of the cranial finite element model.

Recently, surgeons have begun to treat serious congenital craniofacial deformities including craniosynostoses with mechanical devices that gradually distract the skull. As a prospective means of treatment planning for such complex deformities, FE models derived from routine preoperative CT scans (CT/FEA) would provide ideal patient specific engineering analyses. The purpose of this study was to assess the dimensional and predictive accuracy of the CT/FEA process through the development of a 3D model of a dry human calvarium subjected to two-point distraction ex vivo. Comparative skull measurements revealed that CT/FEA construction error did not exceed 1% for transcranial dimensions, and the thickness error did not exceed 8.66% or 0.31 mm. CT/FEA strain predictions for the central region of the skull, between the distraction posts, were not statistically different from homologous gage values at P < 0.05. Peripherally, however, the strain fields were less well behaved and the FE predictions showed only general qualitative agreement with gage recordings.

Clomipramine challenge responses covary with Tridimensional Personality Questionnaire scores in healthy subjects.

Cloninger's Unified Biosocial Theory of Personality postulates a relationship between the relative functional activity of central serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, and the strength of three elemental dimensions of personality. These dimensions are Harm Avoidance, Novelty Seeking, and Reward Dependence, respectively. Accordingly, we predicted that neuroendocrine responses to serotonergic challenge would correlate with Harm Avoidance scores, but not with Novelty Seeking or Reward Dependence scores. We examined the relationship between the prolactin and cortisol responses to a 12.5-mg intravenous clomipramine challenge and these personality dimensions as measured by Cloninger's Tridimensional Personality Questionnaire in 32 healthy subjects. The cortisol response correlated only with Harm Avoidance scores, as predicted; however, prolactin response did not correlate with Harm Avoidance scores. Instead, it demonstrated an inverse relationship with Novelty Seeking scores. There was a positive relationship of baseline prolactin with Harm Avoidance in a post hoc analysis. Cortisol response to serotonergic challenge may be a better indicator for responsivity of serotonergic systems as they relate to the personality dimension of Harm Avoidance than is prolactin. Prolactin responses may be overly affected by dopaminergic influences; however, baseline prolactin may still be a valid indicator of serotonergic tone.

The effects of age, gender, and season on serotonergic function in healthy subjects.

1. Several factors, including age, gender, and season of the year, have been reported to affect physiologic indices of central serotonergic function, although some of these findings have not been consistent across groups of subjects and types of serotonergic measures. 2. The authors investigated the role that each of these variables might play in the neuroendocrine response to acute intravenous challenge with the serotonin reuptake inhibitor clomipramine (CMI) in healthy volunteers. 3. Thirty seven healthy subjects (17 women and 20 men), with an age range of 19 to 50 years, received 12.5 mg of CMI intravenously under standardized conditions. 4. The maximum change from baseline in plasma prolactin concentrations ("delta-max") was significantly related to age, after controlling for gender and season. 5. In contrast, neither gender nor season was significantly related to prolactin delta-max, after controlling for the other two variables. 6. Although the age range and sample size are relatively limited, the results from this study suggest that age, but not gender or season, may influence serotonergic function, as measured by the prolactin response to CMI challenge.

The impact of an electroconvulsive therapy consultation service on ECT use at a university teaching hospital.

In order to test the hypothesis that the establishment of a centralized electroconvulsive therapy (ECT) consultation service would affect ECT use at a university teaching hospital, we retrospectively reviewed medical records of patients who received ECT during two 12-month periods preceding and following the institution of a comprehensive ECT consultation service. Data regarding ECT usage, including utilization, types of patients treated, and lengths of stay, were obtained. Patients treated after the institution of a comprehensive ECT consultation service received ECT with less delay, were discharged more quickly after the conclusion of ECT treatment, and had shorter lengths of stay compared with patients who received treatment before the initiation of the service. Following the establishment of the ECT service, the absolute number of patients who received ECT increased, although the rate of ECT use did not change. These findings suggest that the establishment of a comprehensive ECT consultation service may lead to more efficient use of this important treatment in university hospitals and to more cost-effective treatment of some patients with major depression. Additional research is necessary to explore the generalizability of these findings to other treatment settings.

6-sulfatoxymelatonin levels in pregnant women during workplace and nonworkplace stresses: a potential biologic marker of sympathetic activity.

Melatonin production is regulated by both catecholamines and sympathetic activity. Urine levels of the major metabolite of melatonin, 6-sulfatoxymelatonin, correlate well with serum melatonin levels and have been used to evaluate sympathetic output. We tested the hypothesis that urinary levels of 6-sulfatoxymelatonin would reflect the change in adrenergic activity on working days compared with nonworking days during pregnancy. Twenty-three healthy pregnant women, employed in a variety of occupations, including physicians, nurses, secretaries, salespeople, and laboratory workers were recruited from the clinics of the University of North Carolina School of Medicine. We measured 6-sulfatoxymelatonin levels in first morning voids and for the subsequent 10 hours at 24, 28, 32, and 36 weeks' gestation. Urine was collected in sets during working days and during nonworking days. 6-Sulfatoxymelatonin was measured by radioimmunoassay. In 11 women we also measured urine catecholamines by high-performance liquid chromatography. Levels of 6-sulfatoxymelatonin output did not change across gestation, although they tended to drift down as pregnancy progressed. Median levels at first morning void were 6.3 micrograms on workdays and 4.6 micrograms on nonworkdays. Although all values were skewed toward work being greater than nonwork, there were large interindividual variations. We therefore compared subjects against themselves and compared work levels for each subject to the corresponding gestational age-matched nonwork value. Among the 23 women, median 6-sulfatoxymelatonin levels were 81% greater during work than nonwork (p < 0.0002) when first morning collections were compared. Daytime urinary excretion of 6-sulfatoxymelatonin on workdays was 38% (p < 0.005) greater than during nonworkdays.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of protein kinases on desensitization of the porcine follicular membrane luteinizing hormone/chorionic gonadotropin-sensitive adenylyl cyclase.

Because the acute homologous phase of desensitization of the LH/CG-sensitive adenylyl cyclase in porcine follicles is readily demonstrated in a cell-free membrane preparation, it follows that any enzyme(s) required to achieve desensitization must be present in the membranes and must be activated upon LH/CG receptor activation. The purpose of the following studies was to determine whether modulation of endogenous membrane protein kinases, with activators or inhibitors, or addition of exogenous protein kinases affected desensitization of the LH/CG-sensitive adenylyl cyclase. The effects of these potential modulators were evaluated in both the presence and absence of ligand (hCG)-stimulated receptor activation. To this end, membranes were incubated in the presence or absence of hCG (stage 1) and then assayed for adenylyl cyclase activity in the presence or absence of hCG (stage 2). The results showed that although porcine follicular membranes rich in LH/CG-sensitive adenylyl cyclase activity also exhibited cAMP-dependent [protein kinase-A (PKA)], cGMP-dependent (PKG), lipid-dependent (PKC), Ca2+/calmodulin, and casein kinase-I and -II activities, only full hCG-stimulated adenylyl cyclase activity (measured with BSA in stage 1 and hCG in stage 2) was reduced upon addition of exogenous PKC (to the stage 1 incubation). hCG-dependent desensitization of cAMP synthesis (measured with hCG in stages 1 and 2) was unaffected by activators or inhibitors of endogenous PKA, PKC, or PKG, by an inhibitor of casein kinases and kinases in the beta-adrenergic receptor kinase family, or by the addition of exogenous active PKA, PKC, or rhodopsin kinase to the stage 1 incubation. These results suggest that the acute homologous phase of hCG-dependent desensitization of adenylyl cyclase activity in follicular membranes is not regulated by PKA, PKC, PKG, or messenger-independent heparin-sensitive protein kinases.

Altered prolactin response to clomipramine rechallenge in healthy subjects.

The effect of an initial challenge with the serotonin (5-HT) uptake inhibitor clomipramine (CMI) on subsequent rechallenge was studied in healthy men who served as volunteers. Carefully screened volunteers were assigned to one of three conditions: (1) CMI challenge followed 2 weeks later by CMI rechallenge; (2) placebo challenge followed 2 weeks later by CMI challenge; and (3) CMI challenge followed 4 weeks later by CMI rechallenge. We found significant blunting of the prolactin response to CMI rechallenge 2 weeks (Signed Rank = -12, p = 0.05), but not 4 weeks after an initial challenge. Placebo challenge did not effect CMI challenge 2 weeks later. These findings suggest that a single exposure to IV CMI may cause 5-HT receptor changes that are present 2, but not 4 weeks later. The ramifications of this finding with regard to the use of 5-HT challenge paradigms in a test-retest design are discussed.

Central serotonergic changes following antidepressant treatment: a neuroendocrine assessment.

We employed a neuroendocrine challenge paradigm to study the effects of antidepressant treatment on serotonergic systems in depressed patients. We compared the maximum prolactin response to intravenous clomipramine (CMI) in depressed patients who responded to antidepressant treatment to that of nonresponders. Pretreatment baseline prolactin concentrations and pretreatment prolactin responses to clomipramine challenge were not different in responders compared to non-responders. However, following antidepressant treatment, the 6 responders demonstrated a significant change in their clomipramine challenge test results, as indicated by an increase in prolactin responses. In contrast, the 7 nonresponders did not demonstrate a change in their prolactin response to clomipramine challenge following treatment. These data support the hypothesis that serotonergic system dysfunction, as manifested by blunted prolactin response to clomipramine challenge, tends to normalize after successful treatment for depression, and that abnormal serotonergic function may be a state-dependent characteristic.

Reversal of the desensitized state of pig ovarian follicular human choriogonadotropin-sensitive adenylylcyclase by guanosine 5'-O-(2-thiodiphosphate).

We investigated the stability of the desensitized state of the human choriogonadotropin (hCG)-sensitive adenylylcyclase of the pig ovarian follicle. A 20,000 x g membrane preparation of pig follicular membranes was incubated under conditions which resulted in the hormone-induced desensitization of the hCG-responsive adenylylcyclase. The desensitized state was maintained upon subsequent incubation of the membranes with GTP, GDP, GMP, ATP, ADP, AMP, CTP, UTP, adenyl-5'-yl imidodiphosphate (AMP-P(NH)P), and adenyl (beta, gamma-methylene)-diphosphonate (AMP-P(CH2)P); however, the desensitized state was reverted to a fully active state upon incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) and guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). The reversal effect of GDP beta S on hCG-responsive adenylylcyclase activity was time- and temperature-dependent, and showed a selectivity for GDP beta S over adenosine 5'-O-(2-thiodiphosphate) (ADP beta S) (half-maximal effective dose of 12 microM versus 260 microM, respectively). GDP beta S had no effect on the binding affinity or apparent number of luteinizing hormone (LH)/CG receptors or on the dissociation rate of 125I-hCG from the receptor. GDP beta S promoted an hCG- and time-dependent release of guanine nucleotides from the membranes. A model is proposed which accounts for the unique characteristics of LH/CG-sensitive adenylylcyclase desensitization and subsequent reactivation by GDP beta S.