Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients.

A reduction in 5-hydroxyindoleacetic acid in cerebrospinal fluid was found in depressed and manic patients both while they were symptomatic and also after treatment. The concentration of homovanillic acid was initially reduced and then tended to increase after treatment.

Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction.

The regulation of hypothalamopituitary-adrenal (HPA) function in depressed patients was studied by a midnight dexamethasone suppression test. By using an observation period of 24 hours postadministration of dexamethasone, a graded series of abnormal test responses was identified. Depressed patients show abnormal early escape from suppression rather than absolute resistance to HPA suppression by dexamethasone. With increasing severity of depression, this escape occurs progressively more early on the day after administration of dexamethasone. These abnormalities were strongly related to the presence of HPA hyperactivity before dexamethasone was given. The essential disturbance of neuroendocrine regulation in depression is a failure of the normal brain inhibitory influence on the HPA system. This disinhibition of HPA activity suggests that there is an abnormal limbic system drive on the HPA axis in primary depressive illness.

The value of interviewing family and friends in assessing life stressors.

A reliability study of a life events questionnaire administered to 117 pairs of respondents indicated that a "significant other" (family member or friend) added approximately 29% new information to that gathered from the patient alone. A validity check of this information with a "knowledgeable" third party confirmed approximately 80% of the events reported by the subjects and significant others. The findings suggest that studies designed to collect information about the occurrence of specific life stressors would obtain more reliable and no less valid data from separate interviews of patients and significant others, and the pooling of the positive responses obtained from these two sources.

Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients.

Forty-two patients with endogenomorphic depression (ED) and 42 patients with other psychiatric disorders received an overnight dexamethasone test of hypothalamopituitary-adrenal (HPA) suppressibility. Plasma and urinary cortisol measures showed that the ED patients had significantly greater HPA activity before dexamethasone and less complete HPA suppression after dexamethasone. High cortisol vlaues after dexamethasone correlated strongly with spontaneous HPA disinhibition, as indicated by high baseline midnight plasma cortisol levels. Criteria for defining normal suppression responses were developed. All patients with depressive neuroses and most patients with other nondepressive disorders had completely normal responses to dexamethasone. About half of the ED patients had abnormal responses, whether or not they were receiving other drugs at the time of the test. Drug-free patients with depressive neuroses or other disorders showed no abnormal responses to dexamethasone. The effects of psychotropic drugs on the test require further study. Patients with two or more abnormal cortisol values after administration of dexamethasone were identified correctly as ED at confidence levels close to 100%. The dexamethasone suppression test may be of value as a laboratory aid in the diagnosis of "endogenous" depression.

The erythrocyte lithium-plasma lithium ratio in patients with primary affective disorder.

Increasing attention has been given to the significance of intra-cellular concentrations of the lithium ion in patients treated with this drug. The erythrocyte has been the most common cell investigated because of its accessibility and certain similarities between the ion transport mechanisms of this cell and the neuron. Intraerythrocyte lithium is expressed as the ratio of lithium in the cell to the plasma lithium concentration (lithium ratio). The lithium ratio has been reported to be related to a number of clinical variables, including treatment response, clinical state, side-effects, toxicity, diagnosis, and electrophysiological effects. We have investigated the lithium ratio in a large series of patients with a primary affective disorder and in a smaller control group. We found a significantly higher mean lithium ratio in the bipolar diagnostic group than in the unipolar and control groups. There was a trend, not statistically significant, in the unipolar and bipolar groups for females to have higher lithium ratios than males. While not diagnostic, the lithium ratio appears to be another biological variable where bipolar patients, as a group, differ from normals and others with an affective disorder.

Amine precursors and depression.

The amino acid precursors, levodopa and L-tryptophan, were given to a group of hospitalized depressed patients in a double-blind placebo controlled study. Relatively large doses were not associated with sufficient clinical improvement to allow the patients to leave the hospital. Previous studies using the precursor-load strategy have produced conflicting findings on the use of these compounds for depressed patients.

Genetic determinant of lithium ion metabolism. II. An in vivo study of lithium ion distribution across erythrocyte membranes.

A study was conducted to determine if membrane factors, known to influence the distribution of sodium ion (Na) and potassium ion (K), also influence lithium ion distribution. Two groups of sheep with genetically determined differences in their cation concentrations were administered lithium chloride for ten days. The low red blood cell (RBC) potassium ion sheep (LK) had a greater RBC lithium ion concentration than the high RBC potassium ion sheep (HK). In vitro incubation of erythrocytes with lithium chloride also produced substantially different RBC lithium ion: plasma lithium ion ratios similar to those seen in the vivo study. Distribution of lithium ion was generally similar to that of Na ion. It seems that lithium ion distribution may be controlled by the same genetic factors that regulate Na ion distribution.

Multiple hormonal responses to protirelin (TRH) in depressed patients.

The effects of protirelin (thyrotropin-releasing hormone [TRH]) administration on the release of five pituitary hormones (thyrotropin [TSH], prolactin [Prol], growth hormone, luteinizing hormone, and follicle-stimulating hormone [FSH]) were examined in 45 patients with major depressive disorder and 32 healthy volunteers. Although mean pituitary responses to protirelin in depressed patients and controls appeared to be comparable, depressed patients had higher SDs in all cases. Twelve patients (26.7%) but no controls had two or more abnormal hormonal responses to protirelin administration. The use of several nonparametric analyses revealed significant differences in patterns of hormonal response between depressed patients and controls for TSH, Prol, and FSH. These findings support the hypothesis that increased variability of neuroendocrine responsiveness represents a fundamental aspect of physiologic function in patients with endogenous depression.

A.E. Bennett Award Paper. A kinetic analysis of 5-hydroxyindoleacetic acid excretion from rat brain and csf.

Studies of neurotransmitter kinetics based on intraventricular injections of radio-labeled metabolites have been limited by several problems, including the inability of most investigators to recover more than 45% of the infected isotope from brain homogenates within several minutes after the injection...

Cerebral evoked potential changes produced by treatment with lithium carbonate.

To confirm and extend previous findings concerning evoked potential (EP) changes produced by lithium carbonate (Li), 12 depressive patients were studied while on placebo and on therapeutic doses of Li. Four kinds of EPs were recorded from 14 leads: somatosensory (SEP) to left (LSEP) and right (RSEP) median nerve stimuli; visual (VEP) to a checkerboard flash; auditory (AEP) to binaural click. Plasma and erythrocyte (RBC) Li levels and Hamilton Depression ratings were obtained. Li produced a number of amplitude changes in EPs of all sensory modalities, while there were few latency changes; in general, amplitudes of positive components were increased, while negative component amplitudes were reduced. The spatial distributions of EP peaks were mainly unaltered by Li. The amount of EP amplitude change with Li tended to be correlated with plasma and RBC Li levels. No convincing correlations were found between alterations in EPs and depression ratings. The nature of the EP changes with Li was generally not concordant with normalization of the deviant EP characteristics found in depressives. The findings indicate that Li produces more widespread CNS changes than suggested by previous reports; it appears that these tend to be related to Li levels, but not to the therapeutic effects of Li.

Sertraline safety and efficacy in major depression: a double-blind fixed-dose comparison with placebo.

In a 6-week, randomized, double-blind, multicenter trial, sertraline 50 mg, 100 mg, or 200 mg, or placebo, was administered once daily to 369 patients with DSM-III-defined major depression. Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression (HAMD), HAMD Bech Depression Cluster, Clinical Global Impressions (CGI) Severity, CGI Improvement, and Profile of Mood States Depression/Dejection Factor. For the evaluable-patients analysis, all sertraline groups showed significantly (p < 0.05 or better) greater improvements in all efficacy variables except one when compared with the placebo group. For the all-patients analysis, all efficacy variables in the 50 mg group were statistically significantly (p < 0.05) better than placebo. Side effects increased with increasing dosage but were usually mild and well tolerated. The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations.

A placebo-controlled trial of L-365,260, a CCKB antagonist, in panic disorder.

The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.

Prediction of the lithium ratio in man by means of an in vitro test.

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose data.

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dise of desmethylimipramine (DMI) or imipramine (IMI) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady-state plasma levels. In patients receiving DMI there was a correlation (r = 0.97, n = 10) between 24-hr and steady-state DMI levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24-hr and steady-state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a "therapeutic" dosage regimen without delay.

Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam.

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03 mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t1/2) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t1/2 by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding.

Lithium in the treatment of depression.

The author reviews the studies of lithium as an antidepressant, evaluates the evidence that there might be specific subgroup of patients for whom it is effective, and reports a study he and his associates conducted that found lithium to be effective for 13 of 21 depressed patients. He concludes that there is convincing, although not conclusive, evidence for an antidepressant effect of lithium and that only by identifying the subgroup of patients for whom it is effective can the continuing uncertainty surrounding lithium's role in affective disorder be resolved. He also calls for a reevaluation of the relationship between mania and depression.

The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels.

The authors present a clinical approach for predicting and using plasma concentrations of tricyclic antidepressants in the treatment of depressed patients. They review the pharmacokinetics of this group of drugs and their side effects and toxicity. There is a suggested therapeutic range for plasma concentrations of imipramine, amitriptyline, and nortriptyline; more definitive studies are needed to determine the necessary plasma levels for achieving clinical response with the other tricyclic antidepressants (desmethylimipramine, protriptyline, doxepin, clomipramine, impiramine N-oxide, and butriptyline). A more thorough knowledge of the clinical pharmacokinetics of tricyclic antidepressants should lead to more rational use of these drugs, with a higher response rate and fewer adverse reactions.

Primary affective disorder in relatives of patients with anorexia nervosa.

The authors examined the incidence of primary affective disorder (PAD) in relatives of 25 patients with anorexia nervosa and of 25 normal control subjects. Among the relatives of patients with anorexia nervosa, 22% (N = 43) had histories of PAD, while only 10% (N = 17) of the relatives of controls had such histories. Among the PAD relatives of anorectic probands, 34 had histories of unipolar depression and 9 of bipolar affective disorder. These findings provide further evidence of a possible relationship between anorexia nervosa and affective illness.

Toward a rational pharmacotherapy of depression.

The authors review several approaches that show promise for predicting which antidepressant medication will be best for a particular patient and for achieving maximum benefit from each drug. These include delineation of clinical and historical characteristics associated with response to various drugs, use of psychological tests, assessment of biochemical and electroencephalographic parameters, evaluation of mood response to amphetamine, determination of acetylator status, and measurement of plasma tricyclic levels and degree of inhibition of platelet monoamine oxidase. The authors believe that the use of these approaches may improve our ability to help depressed patients.

Erythrocyte concentrations of the lithium ion: clinical correlates and mechanisms of action.

When lithium carbonate is administered to individuals, there is considerable intersubject variation in the extent of accumulation of Li+ by erythrocytes. The primary reason for this is differences in the activity of a Li+-Na+ counterflow system, which, under clinical conditions, removes Li+ from the cell. It appears that some bipolar patients accumulate more Li+ in their red cells than either unipolar depressives or normal controls. The precise clinical characteristics of the bipolar patients who accumulate relatively large amounts of erythrocyte Li+ need to be clarified in future research. Finally, the measurement of red cell concentrations of Li+, in addition to the usual plasma measurement, can be used as an indicator of patient compliance.