Tatsuro Ohta

A link between stress and depression: Shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression

Alteration of tryptophan (TRP) metabolism elicited by proinflammatory cytokines has gained attention as a new concept to explain the etiological and pathophysiological mechanisms of major depression. The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is the main TRP metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression. Furthermore, metabolites of the KYN pathway have neurotoxic/neuroprotective activities; 3-hydroxykynurenine and quinolinic acid are neurotoxic, whereas kynurenic acid is neuroprotective. The hippocampal atrophy that appears in chronic depression may be associated with imbalances in neurotoxic/neuroprotective activities. Because proinflammatory cytokines also activate the hypothalamo-pituitary-adrenal (HPA) axis, these imbalances may inhibit the hippocampal negative feedback system. Thus, changes in the TRP metabolism may also relate to the HPA axis-hyperactivity hypothesis of major depression. In this article, we review the changes in TRP metabolism by proinflammatory cytokines under stress, which is assumed to be a risk factor for major depression, and the relationship between physiological risk factors for major depression and proinflammatory cytokines.

Daytime sleepiness and automobile accidents in patients with obstructive sleep apnea syndrome.

Abstract We evaluated the rate of automobile accidents and daytime sleepiness using the Epworth sleepiness scale (ESS) in 44 patients with obstructive sleep apnea syndrome (OSAS). We defined the automobile accident score as a sum of two points for every one automobile accident and one point for every near‐miss accident. Automobile accidents and near‐misses were found in 54.5% and 50.0% in patients with OSAS. Automobile accident score was significantly correlated with the ESS score (r= 0.56, P < 0.01). Our findings suggest that ESS score may be useful in detecting patients with the potential risk of automobile accidents associated with daytime sleepiness.

Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress.

Isolation and acute environmental change are risk factors in human depression. In the present study, we investigated the differences in the brain monoamine activity of rats between two rearing conditions, isolated and group. Moreover, we examined the responses to novelty stress. Male F344 rats aged 11 weeks were divided into the above two groups. Four weeks later they were further divided into non-stress and stress groups. The latter received 20 min exposure to novelty stress. Isolation significantly changed brain monoamine levels, with the levels of dopamine (DA) in the nucleus accumbens and midbrain, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the midbrain, and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus increasing. Serotonin (5-HT) levels also increased in all brain areas except the raphe nuclei. HVA levels in the raphe nuclei decreased. Novelty stress significantly altered brain monoamine levels. DA, DOPAC, and HVA levels in the prefrontal cortex decreased, as did those of 5-HT in the prefrontal cortex and hippocampus. DA levels in the nucleus accumbens increased. Isolation attenuated the enhanced brain monoamine turnover elicited by novelty stress. The enhanced DA turnover ratio in the prefrontal cortex of the group-reared group was attenuated in the isolated-reared group, and the unchanged DA turnover ratio in the nucleus accumbens of the group-reared group declined in the isolated-reared group. The enhanced 5-HT turnover ratio in the prefrontal cortex, nucleus accumbens, and hippocampus of the group-reared group was attenuated in the isolated-reared group. Isolation may exacerbate adaptation to stress, and be related to the etiology of human depression.

Comorbidity in attention deficit–hyperactivity disorder

Attention deficit–hyperactivity disorder (ADHD) has been noted for its high rate of comorbidity. The present study is the first report in Japan evaluating the proportion of comorbidity in ADHD cases presenting in the clinical setting, aiming at clarifying the picture of ADHD in Japan. The subjects consisted of 68 child and adolescent cases meeting criteria for ADHD (Diagnostic and Statistical Manual of Mental Disorders, 4th edn) under treatment at a child psychiatry clinic (IQ > 50, mental age ≥ 4 years old). Disorders evaluated as comorbid disorders were mood disorders, anxiety disorders, elimination disorders, sleep disorders, tic disorders, oppositional defiant disorder (ODD), conduct disorder (CD), school refusal, and epilepsy. Comorbidity with mood disorders, anxiety disorders, ODD, and CD, were found to be lower than the high rates conventionally reported in North America. The lower age of the present subjects, primarily in infancy and elementary school age with few adolescent cases, and a bias towards milder cases from an outpatient clinic without inpatient facilities are believed to be factors accounting for this disparity. Furthermore, it was a notable fact that mentally delayed cases (IQ: 51–84) amounted to 34% of the cases, indicating the necessity to consider intelligence level when formulating a treatment strategy for ADHD.

Inhibitory action of brotizolam on circadian and light-induced Per1 and Per2 expression in the hamster suprachiasmatic nucleus

Triazolam reportedly causes phase advances in hamster wheel‐running rhythm after injection during subjective daytime. However, it is unclear whether benzodiazepine affects the Per gene expression accompanying a behavioural phase shift. Brotizolam (0.5–10 mg kg−1) induced large phase advances in hamster rhythm when injected during mid‐subjective daytime (circadian time 6 or 9), but not at circadian time 0, 3 or 15. Brotizolam (5 mg kg−1) significantly reduced the expression of Per1 and Per2 in the suprachiasmatic nucleus 1 and 2 h after injection at circadian time 6, and slightly reduced them at circadian time 20. Injection of 8‐OH‐DPAT (5 mg kg−1) at subjective daytime induced similar phase advances with a reduction of Per1 and Per2 expression. Co‐administration of brotizolam with 8‐OH DPAT failed to potentiate the 8‐OH DPAT‐induced phase advances and reduced Per expression. Both phase advance and rapid induction of Per1 and Per2 in the suprachiasmatic nucleus after light exposure (5 lux, 15 min) at circadian time 20 was strongly attenuated by co‐treatment with brotizolam 5 mg kg−1. The present results strongly suggest that reduction of Per1 and/or Per2 expression during subjective daytime by brotizolam may be an important step in causing a behavioural phase advance. The co‐administration experiment suggests that common mechanism(s) are involved in brotizolam‐ or 8‐OH DPAT‐induced phase advances and the reduction of Per gene expression. These results suggest that brotizolam is not only a good drug for insomnia but also a drug capable of facilitating re‐entrainment like melatonin.

MULTI-CENTER STUDY OF SEASONAL AFFECTIVE DISORDERS IN JAPAN : A PRELIMINARY REPORT

A multi-center study on seasonal affective disorder (SAD) was conducted from the autumn of 1988 to the spring of 1989 with the cooperation of 16 facilities in Japan. Forty-six SAD patients were identified among 1104 respondents to our advertisements in mass media, or patients seen at the outpatient clinics. Essentially similar findings to other previous reports were obtained in terms of onset age of the first episode, duration of episode, high proportion of depression in first-degree relatives and atypical vegetative symptoms. However, a nearly equal sex ratio, together with a high proportion of unipolar depression, is characteristic of the present study. Increased appetite and carbohydrate craving were predominant only in female patients, whereas hypersomnia was prominent in both sexes. Effective response to light therapy was found in 17 SAD patients. However, a controlled study on a large number of patients is required to allow final conclusions on the efficacy of light therapy in Japanese SAD patients.

Effects of moclobemide on forced-swimming stress and brain monoamine levels in mice

Moclobemide [Ro 11-1163, p-chloro-N-(2-morpholinoethyl)benzamide, AURORIX] is known as an antidepressant and a reversible inhibitor of type A monoamine oxidase. In the present study, a forced swimming test was applied to mice to evaluate behavioral and neurochemical effects of this drug. During forced swimming posture of immobility, a typical behavioral change, was observed, and biochemical analysis of the brain revealed significant changes in the monoamine levels. The norepinephrine concentration was reduced, while that of its product was increased, indicating increase in norepinephrine turnover. The stress increased the levels of dopamine, serotonin, and their metabolites. Moclobemide significantly improved the immobility elicited by the test, and it could prevent the changes in the turnover of norepinephrine, dopamine, and serotonin induced by the stress. These results suggest that moclobemide may improve the behavioral changes induced by the forced swimming through its effects on monoamine metabolism.

Changes in monoamine levels in mouse brain elicited by forced-swimming stress, and the protective effect of a new monoamine oxidase inhibitor, RS-8359

As a stress model, a forced swimming test was applied to mice; and a typical behavioral change, an immobile posture, was recognized. This affected the brain monoamine levels significantly. The norepinephrine concentration was reduced, while that of its product was increased; and in the case of dopamine, both the amount of the amine and its product were increased. Stress increased the levels of serotonin and its product in the brain. The effects of RS-8359, (±)-4-(4-cyanophenyl)amino-6,7-dihydro-7-hydroxy-5H-cyclopenta[d]-pyrimidine, a new inhibitor of type A monoamine oxidase, on the behavioral and biochemical changes caused by forced swimming were also investigated. RS-8359 significantly improved the immobile posture elicited by the forced swimming test. It reduced the increased turnover of norepinephrine and serotonin systems caused by swimming. These results suggest that the effect of RS-8359 on behavioral and biochemical changes by stress may be mainly due to its effects on norepinephrine and serotonin systems, presumably by the inhibition of type A monoamine oxidase.

Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder

Phototherapy was administered to 24 depressed patients with seasonal affective disorder (SAD), of which 62%, 24%, and 14%, respectively, showed improvements of greater than or equal to 50%, 25-50%, and less than 25% based on the Hamilton rating scale for depression for SAD (HAMSAD). No patients showed aggravation or side effects. Although the improvement rate in HAMSAD correlated significantly with the pretreatment severity of atypical symptoms of depression, it did not correlate with that of typical symptoms. This suggests that phototherapy is a useful treatment in SAD and that responsiveness to phototherapy in SAD can possibly be predicted by the atypical depressive symptoms before treatment.

The plasma tetrahydrobiopterin levels in patients with affective disorders

Tetrahydrobiopterin (BI-L) is the cofactor for the pteridine-de~ndent monoxygenases (phenylalanine tyrosine and tryptophan hydroxylases) (Kaufmann and Fisher 1974), which play important roles in the biosynthesis of biogenic amines such as catecholamines and indolamines. The biosynthesis of these biogenic amines is regulated by the hydroxylat~on reaction of amino acids such as tyrosine and tryptophan (Nagatsu et al. 1964; Lovenberg et al. 1967), and this hydroxylation reaction is regulated by the concentration of BH4 (Kettler et ~J. !974). These biogenic amines, especially noradrenaliE.e and serotonin, have been thought to be related to affective disorders (Van Praag 1982). Therefore, the relationship between BH4 and depression has been of particular interest, and some controversial results about this relationship have been reported: lowering of the BI-L~ synthesi,~ in the postmortem brains of patients with depression (Blair et al. 1984); no difference between the CSF biopterin levels in patients with depression and in normal controls (Kellner et al. 1980; Levine and Lovenberg 1984); an in-