J. Schmider

CEREBROSPINAL FLUID CONCENTRATIONS OF CORTICOTROPIN-RELEASING HORMONE, VASOPRESSIN, AND SOMATOSTATIN IN DEPRESSED PATIENTS AND HEALTHY CONTROLS: RESPONSE TO AMITRIPTYLINE TREATMENT

The effect of amitriptyline upon hypothalamic‐pituitary‐adrenal [HPA]‐system‐regulating neuropeptides (corticotropin‐releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in‐patients. This was followed by a 6‐week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done; eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow‐up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F1,16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t‐test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions. Depression and Anxiety 8:71–79, 1998.

With aging in humans the activity of the hypothalamus-pituitary-adrenal system increases and its diurnal amplitude flattens.

There is compelling evidence for feedback disturbances in the hypothalamus-pituitary-adrenal system associated with human aging as assessed by challenge tests. However, reports about age-related changes in human basal activity are ambiguous and to date little is known about changes in the pulsatile features of the HPA system. To investigate these changes we studied twenty-two healthy male and eleven healthy female subjects ranging from 23 to 85 and 24 to 81 years respectively. 24-hour blood sampling with 30 minute sampling intervals was performed. From 18.00 to 24.00 hours blood was sampled every 10 minutes for analysis of pulsatile features of HPA activity. Statistical analysis revealed that age in particular had major effects upon basal HPA-system activity: there was a significant age-associated increase in minimal (p < 0.0001) and mean (p < 0.02) cortisol plasma concentrations, but no alteration in pulsatile features. We found no age-cortisol correlation during daytime, but were able to demonstrate a strong impact of age upon cortisol plasma levels from 20.00 to 1.30 hours. The diurnal amplitude of cortisol (p < 0.005) and ACTH (p < 0.006), relative to the 24-hour mean of the hormones, showed an age-associated decline. Additionally, the evening cortisol quiescent period (p < 0.01) was shortened in the elderly, suggesting increasingly impaired circadian function in aging. Our results suggest an increased basal activity and a flattened diurnal amplitude of the HPA system in the elderly.

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment

The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.

Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II.

Hypothalamic-pituitary-adrenal system (HPA) function was tested in 24 patients with schizophrenia and compared to 24 age-matched healthy volunteers using the combined dexamethasone-suppression (DST/CRH) corticotropin-releasing hormone stimulation test (DST/CRH). After stimulation with CRH, the dexamethasone-pretreated patients released significantly more cortisol, but a similar amount of adrenocorticotropic hormone (ACTH) in comparison to controls. No association between DST status and degree of severity of illness and/or current medication was found. However, in comparison to unmedicated patients, those patients currently receiving antipsychotics, who were also those with a lesser degree of severity of illness, showed a decreased release of CRH-stimulated cortisol and ACTH. This study demonstrates that schizophrenic patients have a dysregulation of the HPA system as assessed with the DEX/CRH test. Overall, however, the degree of HPA-system dysfunction in schizophrenic patients seems to be of a lesser magnitude than in patients with affective disorders.

Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ).

Extracts of St. John’s wort (Hypericum perforatum) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration–time curve within one dosing interval of amitriptyline by 22% (p = 0.03) and nortriptyline by 41% (p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John’s wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.

Testosterone, gonadotropin, and cortisol secretion in male patients with major depression.

OBJECTIVE Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. METHODS Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22-85 years). RESULTS An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08). CONCLUSIONS Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.

Pulse-Dosing and Conventional Application of Doxepin: Effects on Psychopathology and Hypothalamus-Pituitary-Adrenal (HPA) System

It has been shown that a single pulse-dosing (PD) dose of clomipramine improves depressive symptoms. However, so far PD and conventional (CONV) application of antidepressants have never been directly compared for an extended period. We performed a double-blind study of PD and CONV application of doxepin (DOX) in depressed patients. After a 1-week placebo treatment, nine parents in the PD group received 250 mg of DOX every 6 days and placebo on the other days until day 39. Ten patients in the CONV group received increasing dosages of DOX until day 7 and 250 mg DOX on the other days for 39 days. Three dexamethasone (DEX)-suppression/corticotropin-releasing hormone (CRH)-stimulation tests were completed: (1)during the initial placebo period; (2)on day 9; and (3)on day 21. In the PD group, scores on the Hamilton Rating Scale for Depression (HAM-D) differed from baseline only after day 36 (17.1 +/- 7.0 vs. 22.7 +/- 2.8, p < 0.03). In the CONV group, however, HAM-D scores improved significantly after 2 days (22.8 +/- 7.2 vs. 26.5 +/- 5.7, p < 0.02) and continued to improve until day 39 (7.3 +/- 5.8). From day 25 to 39, there were significant differences between the HAM-D scores of the two groups. In the PD group, the decline of cortisol after DEX pretreatment was nonsignificant (NS) at both follow-up test occasions (35.9 +/- 40.7 vs. 24.0 +/- 20.7 vs. 23.6 +/- 26.6 micrograms/mL). In the CONV group, a significant decrease was observed at the second test (61.8 +/- 61.9 vs. 10.7 +/- 4.2 vs. 19.8 +/- 19 micrograms/mL, p < 0.05, respectively, NS). The area-under-the-curve cortisol response after CRH was attenuated in the PD group (5,667 +/- 2,910 vs. 1,883 +/- 2,178 vs. 2,239 +/- 2,583 [arbitrary unit], p < 0.01, respectively, p < 0.01) and in the CONV group (5,710 +/- 4,734 vs. 1,267 +/- 2,053 vs. 445 +/- 1,016 [arbitrary unit], NS, respectively, p < 0.02. We conclude that CONV application of DOX is clinically superior compared with PD and that both modes of application have attenuating effects on hypothalamus-pituitary-adrenal system activity.

A double-blind comparison of lorazepam and oxazepam in psychomotor retardation and mutism

BACKGROUND An increasing number of case reports indicate a superior therapeutic response of catatonialike symptoms, such as severe psychomotor disturbance and mutism, associated with psychiatric disorder to the benzodiazepine lorazepam (LO). Equivocal results, however, are also reported with regard to other benzodiazepines for the treatment of this syndrome. The purpose of this study was to compare the effects of LO and oxazepam (OX), benzodiazepines with comparable pharmacokinetics, on psychomotor retardation and mutism associated with psychiatric disorder. METHODS Twenty-one hospitalized patients with severe psychomotor retardation and mutism were treated with 2 mg LO and 60 mg OX in a double-blind crossover study design. RESULTS Both benzodiazepines significantly reduced psychomotor symptoms. When administered for the first time, 4 of 7 patients with LO and 6 of 10 patients with OX improved at least 50% on visual analog scale (VAS) rating. Reduction in symptoms was significant with LO and OX treatment on either day of treatment. The second time, however, LO was significantly better compared with OX in alleviating the target symptoms. CONCLUSIONS Both OX and LO are effective for the treatment of psychomotor retardation. Thus, the beneficial effect of LO on psychomotor retardation and mutism is not a unique pharmacodynamic property but more likely due to its pharmacokinetic profile. The differential effect of the two benzodiazepines on the second day of treatment warrants further clarification. Several hypotheses are evaluated.

Borna disease virus proteins in cerebrospinal fluid of patients with recurrent depression and multiple sclerosis

Evidence that human Borna disease virus (BDV) infection is aetiopathogenetically involved in some psychiatric disorders is accumulating, but direct proof for BDV activity in patients’ brains is still lacking. We report BDV proteins (N=40 kDa, P=24 kDa) and antibodies in cerebrospinal fluid (CSF) of 128 patients with psychiatric and 102 with neurological illnesses. Samples originated from a CSF bank (MPI Munich, 1992–1996) and a prospective collection in 1996. Corresponding serum or blood samples were not available. Antigens p40 and p24 (ref 5) were determined by an enzyme immunoassay with mixed specific monoclonal antibodies. These antigens were detected only in CSFs from patients with recurrent major depression and multiple sclerosis, but not in patients with other psychiatric (n=96) or neurological (n=83) disorders (table). Three of 32 patients with recurrent major depression (9·4%) had both proteins in equally high amounts, in the absence of other abnormal CSF findings; two of these had low antibody titres. Samples were collected during the first week in hospital, 6 weeks, 22 weeks, and 52 weeks after onset of their second or third depressive episodes. Two patients had a melancholic subtype and one RESEARCH LETTERS