Carbon monoxide: a critical physiological regulator sensitive to light.

The mechanism by which humans absorb therapeutic light in winter seasonal and nonseasonal depression is unknown. Bright-light-induced release and generation of blood-borne gasotransmitters such as carbon monoxide (CO) may be one mechanism. Here, 24 healthy female volunteers had peripheral blood samples drawn. Samples were collected in a dimly lit room and protected from light exposure. Samples were analyzed for CO concentrations by gas chromatography after 2 h of continuous exposure to darkness vs. bright white light. In a similar confirmatory study, 11 additional volunteers had samples analyzed for CO concentrations after 2 h of continuous exposure to gentle rocking in darkness vs. in bright white light. In the first study, light-unexposed peripheral blood had a mean CO concentration of 1.8 ± 0.4 SD ppm/g. Identically treated samples with 2 h of rocking and exposure to bright white light at illuminance 10,000 lux had a mean CO of 3.6 ± 1.2 ppm/g (p < 0.0001). Post hoc analysis of that study showed that time of day was significantly inversely associated with increase in CO concentration under bright light vs. dark (p < 0.04). In a smaller confirmatory study of 11 healthy female volunteers, after 2 h of rocking, light-unexposed peripheral blood had a mean CO of 1.4 ± 0.5 SD ppm/g. Identically treated blood samples with 2 h of exposure to bright white light at illuminance 10,000 lux had a mean CO of 2.8 ± 1.7 ppm/g (p < 0.02). In conclusion, bright-light exposure robustly increases human blood CO in vitro. This supports the putative role of CO as a physiological regulator of circadian rhythms and light's antidepressant effects. This human evidence replicates earlier data from a preclinical in vivo model. This effect may be stronger in the morning than in the afternoon.

Retinal venous blood carbon monoxide response to bright light in male pigs: A preliminary study.

The physical mechanism by which light is absorbed in the eye and has antidepressant and energizing effects in Seasonal Affective Disorder and other forms of psychiatric major depression is of scientific interest. This study was designed to explore one specific aspect of a proposed humoral phototransduction mechanism, namely that carbon monoxide (CO) levels increase in retinal venous blood in response to bright light. Eleven mature male pigs approximately six months of age were kept for 7days in darkness and fasted for 12h prior to surgery. Following mild sedation, anesthesia was induced. Silastic catheters were inserted into the dorsal nasal vein through the angular vein of the eye to reach the ophthalmic sinus, from which venous blood outflowing from the eye area was collected. The animals were exposed to 5000lx of fluorescent-generated white light. CO levels in the blood were analyzed by gas chromatography before and after 80min of light exposure. At baseline, mean CO levels in the retinal venous blood were 0.43±0.05(SE)nmol/ml. After bright light, mean CO levels increased to 0.54±0.06nmol/ml (two-tailed t-test p<0.05). This study provides preliminary mammalian evidence that acute bright light exposure raises carbon monoxide levels in ophthalmic venous blood.

SAD and the not-so-single photoreceptors.

Research in the last century has demonstrated that light is a critical regulator of physiology in animals. More recent research has exposed the influence of light on human behavior, including the phenomenon of seasonal affective disorder (SAD). Repeated studies have shown that light treatment is effective in this disorder. The molecular mechanism by which the body absorbs the light that has energizing and antidepressant effects is still uncertain. This review presents evidence regarding the role of rod and cone photoreceptors, as well as the role of recently discovered nonvisual neuronal melanopsin-containing photoreceptors. The authors discuss an evolutionary-based theoretical model of humoral phototransduction. This model postulates that tetrapyrrole pigments, including hemoglobin and bilirubin, are blood-borne photoreceptors, regulating gasotransmitters such as carbon monoxide when exposed to light in the eye. Recent studies in an animal model for seasonality provide data consistent with this model. Understanding the molecular mechanisms by which light affects physiology may guide the development of therapies for SAD and other pathologies of circadian and circannual regulation.

Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study.

BACKGROUND: Well-tolerated and effective therapies for bipolar mania are required. AIMS: To evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Patients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks. RESULTS: Mean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7). Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%). CONCLUSIONS: Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia.

OBJECTIVES: To evaluate the tolerability of intramuscular (IM) aripiprazole in patients with agitation associated with dementia. DESIGN: A 24-hour, double-blind, placebo-controlled, randomized study. SETTING: Sixteen healthcare facilities in the United States. PARTICIPANTS: A total of 129 patients with acute agitation associated with Alzheimer's, vascular or mixed dementia in healthcare facilities. INTERVENTION: Patients were randomized to IM aripiprazole (5 mg, 10 mg, or 15 mg) or IM placebo administered in divided doses 2 hours apart. MEASUREMENTS: Safety assessments included adverse event (AE) reporting, vital signs, and electrocardiograms. Preliminary efficacy analyses used the Positive and Negative Syndrome Scale-Excited Component (PEC) scores and Agitation-Calmness Evaluation Scale (ACES). RESULTS: There was greater incidence of AEs with IM aripiprazole (50% to 60%) than IM placebo (32.0%), but over 90% were mild or moderate in severity. The incidence of oversedation was low. PEC scores showed greater improvements in agitation with IM aripiprazole 10 mg and 15 mg compared with IM placebo. CONCLUSION: A total of 10 mg or 15 mg of IM aripiprazole administered in divided doses was safe and well tolerated for treatment of agitation associated with Alzheimer's, vascular, or mixed dementia in long-term care. Preliminary analysis showed greater efficacy compared with IM placebo.

Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.

OBJECTIVE: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). METHODS: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. RESULTS: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. CONCLUSIONS: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.

Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole.

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P

Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of intramuscular (IM) aripiprazole in patients with acute agitation with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or schizo-phreniform disorder. METHOD: Patients were randomly assigned to IM aripiprazole 1 mg, 5.25 mg, 9.75 mg, or 15 mg; IM haloperidol 7.5 mg; or placebo and observed for 24 hours. The primary efficacy measure was mean change in the Positive and Negative Syndrome Scale-Excited Component (PEC) score from baseline to 2 hours after initial dosing. Secondary measures included the Agitation-Calmness Evaluation Scale (ACES) score. The study was carried out at 50 centers worldwide between April 2002 and January 2003. RESULTS: A total of 357 patients were randomly assigned to treatment. Intramuscular aripiprazole 5.25 mg, 9.75 mg, and 15 mg and IM haloperidol 7.5 mg demonstrated significantly greater reduction in the primary efficacy measure versus placebo. These changes were statistically significant as early as 45 minutes for the IM aripiprazole 9.75-mg group, with a trend toward significance (p = .051) at 30 minutes. Intramuscular haloperidol 7.5 mg first showed a significant reduction in PEC score versus placebo at 105 minutes. At 30 minutes, significantly more patients responded (defined as a greater than or equal to 40% reduction in PEC score) to IM aripiprazole 9.75 mg versus placebo (27% vs. 13%, p = .05). Intramuscular aripiprazole 9.75 mg significantly improved agitation, without oversedation, as measured by change in ACES score from baseline to 2 hours versus placebo (p = .003). No patient discontinued the study because of treatment-emergent adverse events. Extrapyramidal symptoms occurred most frequently in the IM haloperidol group. The most common adverse event in IM aripiprazole recipients was headache. CONCLUSION: Intramuscular aripiprazole 9.75 mg is a rapidly effective and well-tolerated alternative to IM haloperidol for the control of agitation, without oversedation, in patients with schizophrenia, schizo-affective disorder, or schizophreniform disorder. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00036127.

Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol.

INTRODUCTION: This double-blind, placebo-controlled study investigated the efficacy and safety of intramuscular (IM) aripiprazole and IM haloperidol for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder. MATERIALS AND METHODS: Four-hundred and forty-eight patients were randomized (2:2:1 ratio) to IM aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo. Patients could receive up to three injections over the first 24 h, with second and third injections administered > or =2 and > or =4 h, respectively, after the first if deemed clinically necessary. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component (PEC) score from baseline to 2 h. RESULTS: Mean improvement in PEC at 2 h was significantly greater for IM aripiprazole (-7.27) vs placebo (-4.78; p<0.001); IM aripiprazole was noninferior to IM haloperidol (-7.75) on PEC. All secondary efficacy measures showed significantly greater improvements at 2 h for IM aripiprazole and IM haloperidol over placebo. Mean number of injections/patient and percentage of patients requiring benzodiazepines were significantly lower for IM aripiprazole vs placebo (p<0.01). IM aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were similar for aripiprazole (1.7%) and placebo (2.3%) and lower than with haloperidol (12.6%). CONCLUSION: These results show that IM aripiprazole is an effective treatment, comparable to IM haloperidol, and well-tolerated for acute agitation in patients with schizophrenia.

Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects.

The oral tyramine pressor test was administered to healthy males during treatment with a selegiline transdermal system (STS; 6 mg/24 h). The tyramine sensitivity factor (TSF) was calculated from the ratio of baseline and on-treatment tyramine pressor doses. The tyramine sensitivity factor value following 9 days of treatment with the selegiline transdermal system was 1.85 +/- 0.10. Extended treatment, 33 days, produced a small, clinically non-meaningful increase in this value. The tyramine sensitivity factor for the selegiline transdermal system was similar to that following treatment with 10 mg/d of oral selegiline capsules but more than 20 times less than observed during tranylcypromine treatment. A larger increase in the tyramine sensitivity factor was observed following extended selegiline transdermal system treatment at a higher dose (12 mg/24 h), which was significantly decreased following coadministration of tyramine capsules with a meal. These results suggest a wide tyramine safety margin for the selegiline transdermal system and provide evidence that the 6-mg/24-h selegiline transdermal system can be administered safely without dietary tyramine restrictions.

Circadian phase shifting, alerting, and antidepressant effects of bright light treatment.

Bright light treatment is the most potent melatonin suppressor and circadian phase shifter and is a safe nonpharmacologic antidepressant for seasonal depression. In addition, bright light treatment may restore performance in conditions of sleep debt and misalignment between peak performance and the athletic event. This article discusses the therapeutic use of bright light treatment, its side effects, and mechanisms of action.

Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings.

BACKGROUND: Bright light therapy was shown to be a promising treatment for depression during pregnancy in a recent open-label study. In an extension of this work, we report findings from a double-blind placebo-controlled pilot study. METHOD: Ten pregnant women with DSM-IV major depressive disorder were randomly assigned from April 2000 to January 2002 to a 5-week clinical trial with either a 7000 lux (active) or 500 lux (placebo) light box. At the end of the randomized controlled trial, subjects had the option of continuing in a 5-week extension phase. The Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective Disorder Version was administered to assess changes in clinical status. Salivary melatonin was used to index circadian rhythm phase for comparison with antidepressant results. RESULTS: Although there was a small mean group advantage of active treatment throughout the randomized controlled trial, it was not statistically significant. However, in the longer 10-week trial, the presence of active versus placebo light produced a clear treatment effect (p =.001) with an effect size (0.43) similar to that seen in antidepressant drug trials. Successful treatment with bright light was associated with phase advances of the melatonin rhythm. CONCLUSION: These findings provide additional evidence for an active effect of bright light therapy for antepartum depression and underscore the need for an expanded randomized clinical trial.

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.

Regional brain metabolic correlates of alpha-methylparatyrosine-induced depressive symptoms: implications for the neural circuitry of depression.

CONTEXT: We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion-induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using alpha-methylparatyrosine (AMPT). OBJECTIVE: To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs. DESIGN, SETTING, AND PARTICIPANTS: Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration. INTERVENTIONS: After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart. MAIN OUTCOME MEASURES: Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms. RESULTS: AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P =.002) and dorsolateral prefrontal (P =.03) cortex and thalamus (P =.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms. CONCLUSIONS: Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.

An open trial of morning light therapy for treatment of antepartum depression.

OBJECTIVE: About 5% of pregnant women meet criteria for major depression. No pharmacotherapy is specifically approved for antepartum depression; novel treatment approaches may be welcome. The authors explored the use of morning bright light therapy for antepartum depression. METHOD: An open trial of bright light therapy in an A-B-A design was conducted for 3-5 weeks in 16 pregnant patients with major depression. The Hamilton Depression Rating Scale, Seasonal Affective Disorders Version, was administered to assess changes in mood. A follow-up questionnaire was used to assess outcome after delivery. RESULTS: After 3 weeks of treatment, mean depression ratings improved by 49%. Benefits were seen through 5 weeks of treatment. There was no evidence of adverse effects of light therapy on pregnancy. CONCLUSIONS: These data provide evidence that morning light therapy has an antidepressant effect during pregnancy. A randomized controlled trial is warranted to test this alternative to medication.

Monoamine depletion in unmedicated depressed subjects.

BACKGROUND: Although significant evidence suggests that diminished monoamine function is associated with clinical depression, catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects or never-depressed control subjects. This study assesses the integrated role of these monoamine systems in depressed patients. METHODS: Unmedicated depressed subjects underwent a 2-week, double-blind, random-ordered crossover study consisting of the following active and control conditions respectively: indoleamine (via tryptophan depletion) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) catecholamine depletion. Ten subjects completed both conditions; two subjects were withdrawn after active testing and one after control testing. RESULTS: Mean Hamilton Depression Rating Scale (HDRS) scores decreased progressively throughout the study days (baseline 26.7 points +/- 1.7 SEM and termination 20.0 +/- 2.4, active depletion; baseline 26.1 points +/- 2.3 SEM and termination 23.2 +/- 2.6, control testing) but did not differ between groups. Only three patients demonstrated 20% or greater increases from baseline HDRS at any point during the observation days. CONCLUSIONS: Overall, results show that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects, thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms.

Effects of light on low nocturnal bilirubin in winter depression: a preliminary report.

BACKGROUND: The light-absorbing pigments involved in the induction of treatment of winter depression are unknown. It has been proposed that circulating bilirubin serves as a photoreceptor, in part because of its similarity to the chromophore of phytochrome, a primary time-setting plant molecule. METHODS: We measured nocturnal bilirubin levels in nine patients with winter depression, and seven age- and gender-matched normal comparison volunteers. RESULTS: Nocturnal bilirubin levels were lower in patients than in controls (p <.02), increased in both groups during the night (p <.0001), and increased in patients after 2 weeks of morning light treatment (p =.0009), which was accompanied by clinical improvement. CONCLUSIONS: Low nocturnal bilirubin levels may be associated with winter seasonal depression.