Baruch Shapira

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

Early and long-term effects of electroconvulsive therapy and depression on memory and other cognitive functions

Twenty-seven medication-free, depressed patients (Research Diagnostic Criteria, endogenous subtype) were administered a comprehensive battery testing memory and other cognitive functions before and after a series of bilateral, brief-pulse electroconvulsive therapy (ECT) administered according to a dosage-titration procedure (8.9 \Pm 1.981 treatments). A subset of patients (N = 14) were reexamined at 1 month and 6 months after the conclusion of the treatment. Anterograde (verbal and visuospatial tasks), as well as retrograde (famous and personal events), memory function was significantly impaired at the end of the ECT series. By 1 month follow-up, performance had improved to pre-ECT (depression) levels on both anterograde and retrograde tasks and exceeded these by 6 months. The memory deficits induced by ECT were not a consequence of generalized cognitive impairment. Furthermore, depression and ECT were shown to independently affect memory, and recovery from depression was not a consequence of the amnestic action of the treatment. The results generally confirm previous reports regarding the nature of ECT-induced memory impairment, in a different language and culture. They suggest that long-term effects of the treatment on memory are even less prominent than previously observed.

Neurochemical mechanisms of action of ECS: evidence from in vivo studies.

Recent advances in receptor pharmacology and in the understanding of intracellular signal-transduction systems have given rise to new theories of the mechanism of action of antidepressant drugs. The relevance of these theories to the antidepressant mechanism(s) of electroconvulsive shock (ECS) is discussed, with a view to increasing understanding of the mechanism of electroconvulsive therapy (ECT). Particular attention is given to results obtained with in vivo methods both in experimental animals and in human subjects.

Hormone responses to fenfluramine and placebo challenge in endogenous depression.

Plasma prolactin and cortisol levels after oral administration of d-l fenfluramine hydrochloride (60 mg) and placebo were examined in 24 endogenously depressed patients and 21 age- and sex-matched normal control subjects in a randomized, double-blind study. Prolactin levels were significantly increased by fenfluramine in both groups, but the response was significantly blunted in the depressed patients compared with the controls. This effect was partially dependent upon elevated baseline cortisol levels in the depressed group and was also influenced by a history of weight loss. Plasma cortisol levels were not increased by fenfluramine in either group. These findings confirm previous reports and suggest that patients with endogenous major depression are characterized by central serotonergic hyporesponsivity. The need to account for baseline effects on hormonal responses to putative serotonergic agents is supported by the findings; however, these effects appear to be less striking when endogenicity is a prominent clinical feature of the depressive syndrome. The apparently complex influence of weight loss on prolactin response to serotonergic challenge remains to be clarified as well as the role played by the bioavailability of the challenge drug and its metabolite.

Lithium modulation of second messenger signal amplification in man: Inhibition of phosphatidylinositol- specific phospholipase C and adenylate cyclase activity

The activity of phosphatidylinositol-specific phospholipase C was significantly reduced in platelets obtained from 20 euthymic manic-depressive patients on therapeutic lithium doses (mean blood level 0.85 mEq/l) compared to an age- and sex-matched group of 36 control subjects. The activities of prostaglandin E1-, aluminum/NaF-, and forskolin-stimulated platelet adenylate cyclase activity were also measured in a similar group of 16 lithium-treated and 22 control subjects. A marked reduction in both postreceptor (aluminum/NaF and forskolin) and receptor-stimulated (prostaglandin E1) platelet adenylate cyclase activity was observed in the lithium-treated group (mean blood level 0.81 mEq/l). These findings support the hypothesis that lithiums therapeutic mode of action in manic-depressive psychosis is mediated by the combined down-regulation of both principal second messenger systems, inositol phosphates and cyclic adenosine monophosphate, by reducing the activity of phosphatidylinositol-specific phospholipase C and adenylate cyclase.

Blunted temperature and cortisol responses to ipsapirone in major depression: lack of enhancement by electroconvulsive therapy

Depression has been shown in some studies to be associated with a reduction in hypothalamic 5-HT(1A) receptor function, as indicated by reduced hormone and/or hypothermic responses to 5-HT(1A) agonists such as ipsapirone. The hypothermic response to ipsapirone was reduced in depressed patients treated with amitriptyline. Hormone and hypothermic responses to 5-HT(1A) agonists were reduced in normal subjects administered specific serotonin reuptake inhibitors. Effects of electroconvulsive therapy (ECT) on 5-HT(1A) receptor-mediated responses in humans have not been reported. In the present work, ten depressed patients and 15 control subjects were challenged with placebo and with 0.3 mg/kg ipsapirone, administered 48 h apart in a randomised double blind design. Hypothermic, growth hormone (GH) and cortisol responses were measured. Seven of the depressed patients were treated with a course of ECT, and placebo and ipsapirone challenges were repeated 24 and 72 h after the last treatment. The cortisol response to ipsapirone was significantly reduced in the depressed patients compared with controls. The hypothermic response to ipsapirone was totally abolished in the depressed patients. When tested after a course of ECT, the seven depressed patients again showed reduced or blunted responses. We conclude that hypothalamic 5-HT(1A) receptor function is reduced in depression. In contrast to the effects of electroconvulsive shock (ECS) on post-synaptic 5-HT(1A) receptor function in animals, which have chiefly been measured in the hippocampus using electrophysiological techniques, ECT in humans does not induce an increase in sensitivity of post-synaptic 5-HT(1A) receptors in the hypothalamus.

Interrelationship of age, depression, and central serotonergic function: evidence from fenfluramine challenge studies.

The purpose of this study was to examine the relationship between age-associated changes in central serotonergic function and abnormalities associated with major depression. Under randomized double-blind conditions, prolactin and cortisol responses to the serotonin-releasing agent d,l-fenfluramine hydrochloride (60 mg orally) and placebo were examined in 30 normal subjects (15 men, 15 women; age range 21-84 years) and 39 patients with major depressive disorder, endogenous subtype (14 men, 25 women; age range 29-72 years). In the normal subjects, a significant Age x Challenge x Time interaction was observed in the prolactin response (p = .03). This was primarily due to the elevated prolactin responses of the younger healthy women. Peak minus baseline (delta) prolactin responses were negatively correlated with age (women, p = .004; men, p = .06). In the depressed patients there was no age-related decline in prolactin response to fenfluramine. When depressed and healthy younger subjects were compared, delta prolactin responses to fenfluramine were significantly blunted in young patients with depression (p = .003) irrespective of the significant effect of gender (p = .01), but not in older depressed patients. Cortisol responses to fenfluramine did not reveal consistent effects of age, gender, or diagnosis. Age-related decline in central serotonergic function may make older individuals more vulnerable to depression and possibly render depressive episodes more frequent, more severe, and less amenable to treatment.

Cerebral hypoperfusion in medication resistant, depressed patients assessed by Tc99m HMPAO SPECT

Functional imaging studies generally show decreased cerebral metabolism and perfusion in depressed patients relative to normal controls, although the location of the deficits varies. We used Tc99m HMPAO SPECT to compare cerebral blood flow in medication resistant, depressed patients and a normal control group. HMPAO uptake ratios (adjusted for age) were significantly lower in the depressed patients in the transaxial slices 4 cm and 6 cm above the orbitomeatal line (OML) on the left side. Examining individual regions of interest (corrected for age and multiple testing), we found significantly lower perfusion in the left superior temporal, right parietal and bilateral occipital regions in the patient group. These findings are in limited agreement with previous HMPAO SPECT studies. Methodological differences between studies, particularly variability in adjusting data for age, lead to a divergence in findings. Future research should seek to standardize protocols and data analysis in order to generate comparable results.

European collaborative project on affective disorders: interactions between genetic and psychosocial vulnerability factors

&NA; Despite strong evidence provided by genetic epidemiology of genetic involvement in the aetiology of bipolar and unipolar affective disorders, the exact nature of the predisposing gene(s) is still being investigated through linkage and association studies. The interaction of susceptibility genes and environmental factors in these diseases is also of fundamental importance and requires proper investigation. Interesting theories have recently been proposed examining the possible role of various chromosomal regions, candidate genes and mutations in affective disorders. Reliable multicentre‐based methodology is currently being employed to examine these theories, with attention given to statistical analysis and the statistical power of the sample. The present article describes the European Collaborative Project on Affective Disorders (ECPAD) ‘Interactions between genetic and psychosocial vulnerability factors’, involving 15 European centres. A description is given of the association and family samples collected for the project and also the methodology used to analyse interactions in the gene‐psychosocial environment. This material provides a powerful tool in the search for susceptibility genes in affective disorders and takes into account non‐genetic aetiological factors. Psychiatr Genet 8:197‐205

Social adjustment and self-esteem in remitted patients with unipolar and bipolar affective disorder: A case-control study

To evaluate social adjustment and self-esteem in patients with unipolar (UP) and bipolar (BP) affective disorder and to examine demographic and clinical correlates of these variables, outpatients with UP and BP disorder in remission for at least 12 months were consecutively recruited and individually matched to control subjects with no personal or family history of psychiatric illness (UP-control matched pairs, n = 23; BP-control matched pairs, n = 27). Subjects completed the Rosenberg Self-Esteem scale (SES) and the self-report version of the Social Adjustment Scale (SAS). UP patients reported significantly worse overall social adjustment than their matched controls (P = .009), specifically in the area of social and leisure activities (P = .0003) and poorer self-esteem (P = .02). When separated by gender, only the female UP group manifested significant findings on the SAS. BP patients reported poorer self-esteem than their controls (P = .04), but were not significantly different on the SAS. Although the patients were not clinically depressed, a worse social adjustment was significantly associated with a higher score on the Hamilton Depression Scale (HAM-D) in both groups. In the UP group, this association was absent when the analysis was limited to patients receiving antidepressant pharmacotherapy. The findings indicate that (1) UP patients, particularly women, experience substantial difficulties in social adjustment, primarily in social and leisure activities, even during stable clinical remission, and (2) in both UP and BP patients, adjustment problems are related to depressive symptoms even though these are minimal in severity.