Volumetric MRI analysis of hippocampal subregions in Cushing's disease: a model for glucocorticoid neural modulation.

Several preclinical studies have demonstrated neuronal effects of glucocorticoids on the hippocampus (HC), a limbic structure with anterior-posterior anatomical and functional segmentation. We propose a volumetric magnetic resonance imaging analysis of hippocampus head (HH), body (HB) and tail (HT) using Cushing's disease (CD) as model, to investigate whether there is a differential sensitivity to glucocorticoid neuronal damage in these segments. We found a significant difference in the HH bilaterally after 12 months from trans-sphenoidal surgical selective resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary micro-adenomas. This pre-post surgery difference could contribute to better understand the pathopysiology of CD as an in vivo model for stress-related hypercortisolemic neuropsychiatric disorders.

Time- and dose-dependent effects of corticotropin releasing factor on cerebral glucose metabolism in rats.

The time course and the relation to dose of locomotor activity and of the regional cerebral metabolic rates for glucose (rCMRglc) were measured in freely moving Sprague-Dawley rats after intracerebroventricular administration of ovine corticotropin releasing factor (oCRF). Motor activity was determined using a familiar photocage cell. rCMRglc was measured, using the quantitative autoradiographic [(14)C]2-deoxyglucose procedure, in 73 brain regions at 10, 30, 90 and 180 min after administration of oCRF 10 microg and at 90 min after oCRF 0.1, 1 and 100 microg. oCRF 10 microg increased motor activity in a sustained fashion and increased rCMRglc with different time courses throughout brain regions. In cerebellar regions rCMRglc increases peaked at 90 min and were sustained up to 180 min. In non-cerebellar regions rCMRglc increases peaked at 90 min but declined thereafter. At lower doses (0.1 and 1 microg) oCRF increased rCMRglc in fewer brain regions (1 and 5 regions affected, average increases 1% and 7%) including cerebellar areas and brainstem sensory nuclei and decreased rCMRglc in medial prefrontal cortex. At the highest dose (100 microg) oCRF induced large and widespread rCMRglc increases in cerebellar, brainstem, hypothalamic, limbic and neocortical areas (40 brain regions affected, average increase 32%). The findings indicate that cerebellar areas and brainstem nuclei are highly sensitive to oCRF and may mediate oCRF autonomic and behavioral effects.

Cognitive impairment and (CTG)n expansion in myotonic dystrophy patients.

BACKGROUND: Myotonic dystrophy (DM) is a genetic multisystemic disease with muscular, endocrine, ocular, cardiac and cognitive impairment. The molecular basis of the disease has been identified in an unstable base triplet (CTG)n repeat located in the 3' untranslated region of the miotonin protein-kinase (MT-PK) gene on the long arm of chromosome 19. Cognitive impairment could be a direct expression of this genetic alteration at the central nervous system (CNS) level rather than a consequence of the neuromuscular impairment. To explore this hypothesis, we tested a group of genetically diagnosed, adult onset DM, of their nonaffected relatives (NAR), of patients with spinal muscle atrophy (SMA), and of normal controls using the Wechsler Adult Intelligence Scale (WAIS). METHODS: Seventeen adult-onset DM patients, 9 NAR, 10 SMA patients and 20 unrelated normal controls (NC) were studied. Clinical, neuromuscular and neuropsychiatric evaluation, which included WAIS and the Schedule for Affective Disorders and Schizophrenia (SADS), were performed on the four groups. DM, NAR and NC were also assessed by a neurophysiological (P300) evaluation. A DNA analysis was performed in DM and in NAR to measure presence and magnitude of CTG expansion. RESULTS: We found a statistically significant difference between verbal (p < .0003), nonverbal (p < .0001) and total (p < .0001) IQ of DM patients compared to IQs of NAR, SMA and NC. Seven out of 11 WAIS subtests were significantly and consistently lower in DM patients compared to SMA and/or NC. In DM patients there was a statistically significant negative correlation between nonverbal (r = -.68; p < .002) and total (r = .59; p < .01) IQ and (CTG)n. Patients with DM had a significantly lower P300 amplitude compared to NAR and NC. CONCLUSIONS: Our study indicates that in DM there is a mild but significant cognitive impairment which correlates with the degree of CTG expansion and it is not dependent on the neuromuscular impairment; however further studies with larger groups of patients and controls are suggested to confirm our results, due to the small sample size and to a possible effect of educational level in our patients.

Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy.

BACKGROUND: Mood disorders have been described as the commonest psychiatric disorders in patients with temporal lobe epilepsy. Secondary depression in temporal lobe epilepsy could be interpreted either as an adjustment reaction to a chronic disease or as a limbic dysfunction. To clarify this issue, a controlled study of psychiatric disorders was conducted in different forms of epileptic and non-epileptic chronic conditions. METHODS: Twenty outpatients with temporal lobe epilepsy, 18 outpatients with juvenile myoclonic epilepsy--a primary generalised seizure disorder--20 matched type I diabetic patients, and 20 matched normal controls were assessed by a structured interview (SADS) and by self rating scales (Beck depression inventory (BDI) and the state and trait anxiety scales STAIX1 and STAIX2). RESULTS: Sixteen (80%) patients with temporal lobe epilepsy fulfilled the criteria for a psychiatric diagnosis at the SADS interview with a significantly higher frequency than patients with juvenile myoclonic epilepsy (22%) and diabetic patients (10%) (P < 0.0001). The most frequent disorder in temporal lobe epilepsy was a mood disorder: 11 (55%) patients with temporal lobe epilepsy had depression compared with three patients with juvenile myoclonic epilepsy and two diabetic patients (P < 0.001). Eight patients with temporal lobe epilepsy with an affective disorder also had a comorbid personality or anxiety disorder. Patients with temporal lobe epilepsy scored significantly higher on BDI, STAIX1, and STAIX2 than the three control groups (P < 0.001, P < 0.01, P < 0.001). CONCLUSIONS: Patients with temporal lobe epilepsy have a higher incidence of affective and personality disorders, often in comorbidity, than patients with juvenile myoclonic epilepsy and diabetic patients suggesting that these psychiatric disorders are not an adjustment reaction to a chronic disease but rather reflect a limbic dysfunction.

Cognitive and psychiatric evaluation of 40 patients with myotonic dystrophy.

We evaluated 40 patients suffering from a severe form a myotonic dystrophy (MD) with neuropsychological (WAIS-R, MMSE) and psychiatric tests (SADS, SRT) for the assessment of cognitive and psychiatric symptoms. We tested 20 normal volunteers as control group. Patients with MD scored significantly, lower on WAIS Full Scale (p less than 0.001), Verbal Scale (p less than 0.001), and Performance Scale (p less than 0.001) and on the MMSE (p less than 0.05) than the controls. 35% of patients met the Research Diagnostic Criteria for a psychiatric diagnosis; 17.5% of them had a depressive disorder. The scores on SADS subscales and on the SRT scale of depression were also significantly higher in patients than in controls. Our data confirm that mental impairment and psychiatric disorders are important clinical manifestations of CNS dysfunction in the severe form on MD.

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.

Intellectual impairment and cognitive evoked potentials in myotonic dystrophy.

Twenty-seven patients with myotonic dystrophy (MD) and 20 control subjects were tested using neuropsychological and electrophysiological measures. MD patients reported significantly lower scores on the Wechsler Adult Intelligence Scale and the Mini-Mental State Examination. P3 amplitude of auditory event-related potentials was significantly reduced in 14 patients. P3 latency was normal. In 13 patients, P3 was not elicited. Our results clearly show the presence of a significant impairment of cognitive functioning, as assessed by psychometric measures, in more than 50% of MD patients. Discriminant function correctly classified 92% of patients, using event-related potentials and neuropsychological variables.

Effects of glucocorticoid antagonism with RU 486 on pituitary-adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion.

Data from our group and others suggest that pituitary-adrenal activation in major depression reflects a defect at or above the hypothalamus which results in the hypersecretion of corticotropin-releasing hormone (CRH); some have suggested, however, that elevated indices of cortisol secretion and lack of suppressibility to dexamethasone may be a manifestation of a primary defect in glucocorticoid receptor activation. We report here a study of early morning pituitary-adrenal responses to the glucocorticoid antagonist RU 486 in patients with major depression and healthy volunteers. Previous data suggested that the response to RU 486 could represent an index of endogenous CRH secretory activity. RU 486 produced a robust increase in plasma corticotropin (ACTH) and cortisol secretion in both control subjects and depressed patients. In the controls, however, the increase was confined to the last 2 hours of sampling (6 to 8 am), whereas in the depressed patients the increase occurred throughout the sampling period (3 to 8 am). The ACTH response in the depressed patients exceeded that in the controls during most of the sampling period, including a significant (p less than .005) increase between 3 and 4:30 am. These results are compatible with the idea that hypercortisolism in major depression represents an alteration in the overall set point for hypothalamic CRH secretion rather than a primary alteration at the level of the glucocorticoid receptor.

Stress-responsive neurohormonal systems and the symptom complex of affective illness.

The role of stress in the natural history of major depression has been a subject of intense scrutiny, particularly in light of the 20th century discoveries of some of the biological mediators of stress responses. In this paper we present evidence suggesting the hypothesis that an abnormality in the counterregulation of generalized stress responses underlies critical aspects of the pathophysiology of major depression. In particular, we focus on the role of inadequate glucocorticoid restraint of the central nervous system (CNS) components of the adrenocortical and adrenergic systems, i.e. the corticotropin releasing hormone (CRH) components of the adrenocortical and adrenergic systems, i.e. the corticotropin releasing hormone (CRH) and locus ceruleus-norepinephrine (LC-NE) systems. We believe that this hypothesis not only helps explain many of the observed abnormalities in the syndrome of major depression, but also provides a biological basis for subtyping this syndrome.

Multiple-dose pharmacokinetics of imipramine and its major active and conjugated metabolites in depressed patients.

Imipramine (IMI) and its active metabolites, desipramine (DMI), 2-hydroxyimipramine (2-OH-IMI), and 2-hydroxydesipramine (2-OH-DMI), were assayed by high pressure liquid chromatography in the serum and urine of 14 depressed patients after 1 week of twice-daily treatment with 100 mg of IMI. The concentrations of the glucuronide conjugates of 2-hydroxyimipramine (GA-O-IMI) and 2-hydroxydesipramine (GA-O-DMI) were assessed via enzyme hydrolysis. The range of serum concentrations of IMI and DMI was 65 to 1,064 ng/ml with slight elevation in total active components caused by inclusion of the unconjugated hydroxy metabolites. The average of total active compounds in smokers (239 ng/ml) was less (p less than 0.1) than in nonsmokers (524 ng/ml). The mean serum concentration ratios were 0.24 for 2-OH-IMI/IMI and 0.50 for 2-OH-DMI/DMI ratios, whereas the DMI/IMI ratio was 1.88, indicating more extensive accumulation of DMI. Appreciable glucuronide conjugate accumulation occurred with average serum concentration ratios of 8.13 for GA-O-IMI/2-OH-IMI and 6.22 for GA-O-DMI/2-OH-DMI. Covariance occurred in metabolite/precursor ratios indicating intrapatient similarities in formation/disposition rates of the hydroxy pairs and the conjugate metabolite pairs. Renal clearances of 2-OH-DMI were 35 to 267 ml/min, whereas those of the conjugates were only 10 to 110 ml/min. Total urinary recovery of these metabolites was similar to that reported previously for single IMI doses. The data indicate accumulation of substantial serum concentrations of glucuronide conjugates after therapeutic doses of IMI in depressed patients and similarities within patients in disposition of metabolite pairs.

[Affective disorders in general hospitals: the organic affective syndrome]. / I disturbi affettivi in ospedale generale: la sindrome affettiva organica.

After a survey of the literature on secondary depression and mania caused by physical illness or drugs, a retrospective study on 77 inpatients (seen in the hospital psychiatric consultation service) is reported. Forty per cent of patients presented a diagnosis of depression; 58% of depressed patients had at least one of the "risk factors" for secondary depression (physical illness and drugs known to cause affective disturbances) compared to 24% and 16% of patients with other or no mental disorders (p less than 0.05).

Research diagnostic criteria (RDC) mental disorder and self-reported symptoms in outpatients with complex partial seizures (CPS).

Fifteen outpatients with complex partial seizures (CPS) were investigated to assess the presence and severity of affective disorders, anxiety, and cognitive deficits. Forty percent of patients met the criteria for an affective disorder according to Research Diagnostic Criteria (RDC). Patients scored significantly higher than controls on the Beck Depression Inventory (p less than 0.001), on the State and Trait Anxiety Inventory (p less than 0.01, p less than 0.05), on the Symptom Questionnaire scales for anxiety (p less than 0.005), depression (p less than 0.01), and somatization (p less than 0.01). They also scored significantly lower than controls on the Mini-Mental State Examination for grading cognitive state (p less than 0.05). Epileptic patients with RDC diagnosis of depression reported significantly more symptoms of depression, anxiety, somatization, and less sociability and trustfulness than epileptic patients without concurrent mental disorders. Implications of these results are discussed.

Rating depression in normals and depressives: observer versus self-rating scales.

Different methods of assessing depression and anxiety were tested in 20 patients suffering from a major depressive disorder with melancholia and 20 matched control subjects. Depressives were assessed before and after treatment with amitriptyline and normals were retested at the same interval. The scales used were: Paykel's Clinical Interview for Depression--which is an expanded version of the Hamilton Depression Rating Scale; the Brief Depression Rating Scale; and Symptom Questionnaire (SQ). All scales discriminated sensitively between patients and normals and the scores changed substantially with treatment. Except for the well-being subscales of the SQ, the scales showed an adequate test-retest reliability in normals. Although all scales were suitable for the measurement of depression, they differed in psychometric properties. For example, the Depression subscale of the SQ showed an unusually high test-retest reliability in normals, whereas the Contentment subscale was unreliable. Yet, the latter has been found to be highly sensitive in detecting differences between the effects of psychotropic drugs and placebo in drug trials, so it appears to measure sensitively a fleeting mood. The combined use of all three scales in patients with affective disorders yields information that might not be revealed if only one scale is used.

Hostility and recovery from melancholia.

Twenty inpatients suffering from major depressive illness with melancholia were administered the hostility subscale of the Kellner Symptom Questionnaire and Paykel's Clinical Interview for Depression before and after treatment with amitriptyline. A matched control group of normal subjects had the same assessments at two points in time. Hostility decreased and friendliness increased in depressives after amitriptyline; upon recovery, there were no significant differences in hostility between depressed patients and control subjects, whereas such differences were striking during the illness. Patients who had reported losses before onset of illness rated themselves as more friendly than the other depressives; their hostility did not significantly decrease with recovery. The results suggest that hostility improves with the treatment of depression; life events appear to influence the degree of hostility in depressive illness as well as the response to treatment.

Hypochondriacal fears and beliefs in DSM-III melancholia. Changes with amitriptyline.

The authors administered the Illness Attitude Scales, which identify hypochondriacal patients, to 20 nonpsychotic inpatients with DSM-III diagnosis of melancholia before and after 4 weeks of treatment with amitriptyline, and to a matched group of normals. Before treatment characteristic hypochondriacal responses occurred in over one-third of melancholics whereas after treatment the number was the same as in normals. The findings are in accord with the clinical observation that melancholia is one of the causes of hypochondriacal fears and beliefs and these tend to remit with recovery from depression.

Emotions and personality in complex partial seizures.

Using the emotion profile index (EPI) and the Bear and Fedio personality inventory (PI), we investigated the influence of hemispheric localization of epileptic foci on emotions and personality in 24 patients with complex partial seizure. On the EPI, left patients showed a paranoid and depressed personality and gave a negative image of themselves, whereas right patients rated themselves in a positive way. On the PI, left and right patients showed an epileptic behavioral syndrome. Left patients were more depressed, guilt-ridden and aggressive than right patients.

The dexamethasone suppression and metyrapone tests in depression.

The dexamethasone suppression test (DST) and the metyrapone test (MT), a useful and reliable procedure for assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, were performed in 28 patients suffering from major depressive illness with melancholia. The relationship between the DST and MT appeared to be complex. Patients who failed to suppress cortisol secretion after dexamethasone administration had higher postmetyrapone cortexolone levels and cortexolone/cortisol ratios than suppressors. However, there was a wide range of metyrapone responses in patients exhibiting abnormal DST results. This suggests that failure of adequate suppression after 1 mg of dexamethasone in depressed patients does not necessarily reflect homogeneity in the HPA axis disturbances of such patients.

The metyrapone test in schizophrenic patients and healthy subjects.

The metyrapone test, a useful and reliable procedure for assessing hypothalamic-pituitary-adrenocortical (HPA) axis function, was applied to schizophrenic patients and healthy controls. 4 out of 18 patients had subnormal responses to metyrapone whereas there were no such cases in the 22 control subjects. 1 schizophrenic patient and 3 control subjects had high normal responses to metyrapone. The relationship with the dexamethasone suppression test was found to be complex. These preliminary results suggest that the HPA axis activity patterns in psychiatric illness may be more complicated than previously reported.

The metyrapone test in depressed males.

Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis in depression has received considerable attention, particularly in the now numerous studies utilizing the dexamethasone suppression test. The possibility of HPA axis hypoactivity in this population however has not been similarly explored. To examine this latter possibility, the metyrapone test, a well-established neuro-endocrine assay for determining pituitary reserve, was administered to ten endogenously depressed males and ten matched controls. Consistent with the findings of an earlier study on ten female depressives, one of the depressed males but none of the controls showed clear evidence of HPA axis hypoactivity. This suggests that HPA axis dysfunction in depressives may be more complex than originally anticipated. This finding also has implications for the psychiatric symptomatology classically associated with such illnesses as Addison's disease.