AS RECENTLY as 1900, tuberculosis, influenza, and pneumonia were the leading causes of death in our country (1). For the most part, however, these infectious diseases, as well as those of poor hygiene or undernutrition, no longer plague us. Instead, we succumb most frequently to heart disease and cancer, diseases of slow degeneration (1). Most of all, unlike so many in the generations before us, we are in a position to age. Regardless of what else occurs, we age, we become more constrained by the discrepancy between what we were and what we have become, and each step becomes harder. The goal in the study of aging is not to halt the process, because we can no more be cured of aging than of birth. The goal, instead, is to slow and soften the sharpest edges of the biological unraveling that constitutes aging. Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to...

The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis*

Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stre...

The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis

• Present clinical and research methods of differential diagnosis of schizophrenia and affective psychoses rely very heavily on presenting symptoms and signs, especially in acute psychosis. We have reviewed studies bearing on this issue, including studies of the phenomenology of psychotic illness, outcome, family history, response to treatment with lithium carbonate, and cross-national and historical diagnostic comparisons. We conclude that most so-called schizophrenic symptoms, taken alone and in cross section, have remarkably little, if any, demonstrated validity in determining diagnosis, prognosis, or treatment response in psychosis. In the United States, particularly, overreliance on such symptoms alone results in overdiagnosis of schizophrenia and underdiagnosis of affective illnesses, particularly mania. This compromises both clinical treatment and research.

Diagnosis in schizophrenia and manic-depressive illness: a reassessment of the specificity of 'schizophrenic' symptoms in the light of current research.

• A modified dexamethasone suppression test (DST) has had unprecedented evaluation among biologic tests proposed for clinical use in psychiatry. It has not proved to reflect pathophysiologic changes at the level of the central nervous system or pituitary, and tissue availability of dexamethasone itself may contribute to test outcome. The sensitivity of the DST in major depression is limited (about 44% in over 5,000 cases) but is higher in psychotic affective disorders and mixed manic-depressive states (67% to 78%). The high specificity of the DST vs control subjects (over 90%) is not maintained vs other psychiatric disorders (77% specificity overall), and acute "distress" may contribute to nonsuppression of cortisol. The test may have power in differentiating severe melancholic depression, mania, or acute psychosis from chronic psychosis (87% specificity) or dysthymia (77% specificity). The DST status adds about 11% to the prediction of short-term antidepressant response. Suggestions that failure to maintain normal suppression of cortisol predicts poor outcome are not secure. Uncritical enthusiasm or excessive skepticism regarding the DST are unwarranted.

The Dexamethasone Suppression Test for Diagnosis and Prognosis in Psychiatry: Commentary and Review

Depression occurs in around 35% of patients with Parkinson disease (PD) and is often persistent. Symptoms of depression can be evident in individuals at the time of diagnosis and might develop in the premotor stage of the disease. The underlying mechanisms of depression in PD are not known in detail, but changes in brain structure, signaling by neurotransmitters, and levels of inflammatory and neurotrophic factors are all suggested to contribute to its development. Psychosocial factors and pain could also have roles in depression. Changes in dopaminergic, noradrenergic and serotonergic systems in patients with PD might help to explain the incidence of depression in these individuals. Antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for treating depression in PD. However, antiparkinsonian drugs might have beneficial effects not only on the motor symptoms of disease, but also on a patient's mood. Deep brain stimulation can worsen depression in some patients, but a preliminary study has suggested that transcranial magnetic stimulation could improve symptoms of depression. This Review describes the frequency and course of depression in patients with PD. The mechanisms that underlie depression in this disease are also discussed, and the management strategies for these patients are highlighted.

Depression in Parkinson disease—epidemiology, mechanisms and management

The dexamethasone suppression test (DST) was performed on 21 patients with dementia of the Alzheimer type (DAT), 11 patients with multi-infarct dementia (MI) and 14 healthy controls. Twelve of the DAT patients and eight of the MI patients showed abnormal lack of suppression, compared with just one member of the control group. Abnormal DST was related to dementia as such and not to age or depression, or to levels of CSF monoamine metabolites. Basal serum prolactin concentrations were not increased.

Dexamethasone Suppression Test and Serum Prolactin in Dementia Disorders

The biochemical basis of major depression (MD) in Parkinson's disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks' of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.

Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression

As regards the duration of the observation times, our experience of lithium is in no way comparable with that of our Danish colleagues. To a certain extent, however, we have used the substance on indications other than those usually motivating this therapy, and it is with the experience gained in this connection that this preliminary report deals. T h e astonishingly good results we attained by applying the treatment to manic states led us perhaps into a certain ’lithiomania’, and we began to try out the drug on various severe pathological states that had proved resistant to other measures. Our criterion for considering a case to be treated on atypical indication is the following: the existing picture has not permitted of the diagnosis manic-depressive psychosis before the therapeutic experiment. In several cases a positive result of the lithium therapy has led us to suspect that this diagnosis had as a matter of fact been correct. We shall revert tc, the question of such a diagnosis ex juvantibus after the case histories. The number of cases treated on atypical indication amounts to 27, 15 women and 12 men. In 9 of these cases we observed no effect whatsoever. These formed a group of patients with very varying symptomatology and we shall not at this stage give the case histories. There was a phasic course in 4 of the cases. The group is of course interesting as comparative material, but it is as yet so small that we refrain for the time being from making comparisons. There remain 18 atypical cases in which what we considered a distinct effect was observable, sometimes modest, sometimes very striking. We give a brief account of the 1 8 cases, though in the first and last we go into somewhat greater detail as they are particularly illustrative.

Lithium treatment on atypical indication

In a previous double-blind, 3-week study we compared the effect of clomipramine + placebo with clomipramine + tryptophan in 24 patients with endogenous depression. The patients in the latter group showed a significantly more rapid improvement than those in the former group, especially with regard to the depression-anxiety cluster of symptoms.



These results prompted us to perform a similar study in which zimelidine, a more specific inhibitor of 5-HT reuptake, was used instead of clomipramine. In other respects the design was practically identical to that used in the previous study.



Unexpectedly, tryptophan in combination with zimelidine, was not superior to placebo + zimelidine with respect to antidepressant activity. In comparison with the previous study, the antidepressant action of zimelidine showed no statistically significant difference from clomipramine. However, the patients tended to show a more prompt response after zimelidine + placebo than after clomipramine + placebo. The changes in CSF amine metabolites were likewise different in the two studies. In the two studies taken together 12 out of 49 patients showed prompt improvement within one week. This raises the question whether the therapeutic response to antidepressant drugs necessarily involves a delay as is generally assumed. Side effects were remarkably few and mild in the second study.

Jan Wålinder

Papers

Dexamethasone Suppression Test and Serum Prolactin in Dementia Disorders

Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression

Lithium treatment on atypical indication

5-HT reuptake inhibitors plus tryptophan in endogenous depression.

Recurrent familial psychosis of the schizo-affective type.