Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.

The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO-/-) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg-1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO-/- mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO-/- mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.

Unmet needs of remand prisoners.

A needs assessment protocol which examines 11 problem areas was devised. This was administered to 277 prisoners on remand at Brixton Prison. We found high levels of unmet need for housing, treatment of substance abuse and neurotic symptoms. Twenty-nine per cent were transferred to hospital under the provisions of the Mental Health Act and about a third of those at liberty to do so complied with a discharge plan. Diversion and discharge planning can potentially meet the unmet needs of remand prisoners.

Elderly offenders. A study of age-related factors among custodially remanded prisoners.

Among custodially remanded male prisoners from Greater London and its surrounds, in 1979-1980, nearly 3% (63 men) were aged 55 or over, about one third of these being over 65. More than 40% were detained on theft charges and few for more serious offences, although serious violence was not unknown and nearly one-fifth of those 65 or over were subsequently convicted of non-violent sexual assaults. Like their younger counterparts, less than one-fifth of those aged 55 or over appeared to be first-time offenders. About half of the men of 55 or over had active symptoms of psychiatric disorder on entering the prison and about half had some form of physical disorder, twice the rates for those under 55. Psychosis and alcoholism were the major psychiatric problems; 27% were alcoholics, to the extent of showing withdrawal symptoms on or soon after entering prison. Schizophrenia was less common than the younger age groups, but affective psychosis more so; 37% of the older men had a major functional psychosis. Two-thirds of the 55-64 age group and over three-quarters of the over 65s were without an address; most of both groups were personally isolated.