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In this case report we describe a 44 year old man who developed a transient increase of CSF protein in association with a course of electroconvulsive therapy for depression. Neurological evaluation failed to show any other abnormalities. The finding seems to reflect a transient dysfunction of the blood-brain barrier.

Recent advances in psychiatric research methodology promise major progress. Simultaneously, however, mounting concerns about ethnics of human experimentation have resulted in increased scrutiny and regulation that threaten scientific productivity. Virtually no systematic data have been gathered about the effects of research participation on treatment outcome or patient satisfaction. In this study 56 hospitalized depressed patients, who had agreed to participate in psychobiological research protocols, were then randomly assigned to treatment on a research unit or on standard adult inpatient (nonresearch) units. Research participants received more diagnosis-related somatic treatments, had a longer mean length of stay, and experienced trends toward greater symptom reduction and better consumer satisfaction. We conclude that research participation may be helpful to patients but that more systematic study is needed to help to resolve ethical questions and to assist risk-benefit evaluations.

Antipsychotic drug use may be associated with clinically significant cardiovascular side effects and rare instances of sudden death. The authors review case reports of patients who suddenly died while taking these drugs and examine possible mechanisms involved. Clinical recommendations for prevention are made and include attention to predisposing medical factors and avoidance of risky drug combinations.

The authors took multiple serum samples for measurement of melatonin between 4:30 p.m. and 7:30 a.m. in seven male depressed patients with melancholia and five healthy male control subjects and found that melancholic patients had a significantly lower rise of melatonin. They also compared a second, separate group of 14 women and five men suffering from melancholic depression with seven healthy male control subjects and nine depressed women without melancholia. The melancholic patients had a significantly lower concentration of serum melatonin at 11:00 p.m. than either the control subjects or the nonmelancholic depressed patients. These findings support the possibility that the functioning of the pineal gland is altered in these patients.

Fifty-five (55) depressed patients were treated with amitriptyline (AMI) or imipramine (IMI). Concentrations of AMI, IMI, and their metabolites, nortriptyline (NT) and desmethylimipramine (DMI), were measured in cerebrospinal fluid (CSF) and plasma at steady state by gas chromatography mass spectrometry (GC/MS). Highly significant correlations between CSF and plasma levels of AMI, NT, IMI, and DMI were found (r greater than 0.75; P less than 0.0001 in all cases). There were no significant sex, diagnostic subgroup, or geographic difference in any of the drug parameters measured. An evaluation of the relationship between CSF levels of drug variables and clinical response showed essentially no significant correlations between these various parameters. The results obtained do not support the concept of a 'therapeutic window' for levels of plasma NT in AMI-treated patients. Furthermore, the highly significant correlations between CSF and plasma compartments in terms of drug and metabolite levels would argue against the need to measure CSF levels of these parameters in clinical practice. Plasma level measurements should be equally informative, and simpler to obtain.

Twenty-two patients with recurrent affective disorders received 1-mg dexamethasone suppression tests (DSTs) during multiple hospitalizations. Interepisode consistency of DST results was found in 82% of the subjects, which supports the use of this test as a predictor of relapse.

Erythrocyte/plasma lithium ratios were determined in 41 polar manic depressive outpatients maintained on lithium for a mean of 64 months. Sixteen patients experienced affective episodes requiring additional pharmacologic intervention during periods when their plasma lithium averaged 0.7 meq/l or above for at least 3 preceding months and they were on no concurrent medication known to induce depression or mania. These patients considered to be a homogeneous group of non-responders to lithium, had a mean lithium ratio of 0.50 (range 0.15-1.16). Seven patients experienced affective symptoms at plasma levels below 0.7 meq/1 and/or while taking concurrent medication known to induce affective symptoms, and therefore could not be categorized clinically as lithium non-responders or responders. Eighteen remaining patients, who had no affective episodes during lithium maintenance, were found to have a mean erythrocyte/plasma ratio of 0.52 (range 0.19-1.05). This latter group of apparent responders should be considered heterogeneous in that it may include spontaneous remitters. The difference in mean ratios between the non-responder group and the apparent responder group was not statistically significant. These findings support the contention that the erythrocyte/plasma lithium ratio does not correlate with response of bipolar outpatients to maintenance lithium.

Three separate lithium chloride doses, calculated according to body weight, and a placebo were administered under double-blind conditions to 68 manic inpatients. The relationship of lithium chloride treatment dose to steady-state serum lithium levels (day 7 to 10 of treatment) and clinical response were examined. High (0.72 mEq/kg/day) and medium (0.5 mEq/kg/day) lithium chloride doses were more efficacious than placebo (P<.001 and P<.05, respectively), as determined by decrements in global mania ratings (day 7 to 10 of treatment). A low dose (0.24 mEq/kg/day) was not found to be more efficacious than placebo. The proportion of patients with improved manic ratings increased markedly as a function of increased steady-state serum lithium level(chi-squared for trend in proportions, 17.91; P<.001).

It is unclear why delusional depressives respond poorly to usual doses of tricyclic antidepressants alone. Seventeen elderly, delusional depressives were treated with high doses of imipramine or desmethylimipramine while monitoring plasma levels in an open study. Four of seven patients who received an adequate trial responded, but over half of the total sample had to be dropped due to intolerable side effects or worsening clinical condition. Antidepressants in high doses may be effective for part of the delusional depression sample, but this potentially effective pharmacologic therapy is not feasible in a large percentage of elderly or agitated patients.

Antidepressant drugs in the treatment of chronic depressions have received little systematic study. We used a two-week, single-blind placebo washout followed by a six-week, double-blind comparison of imipramine hydrochloride and placebo in a sample of 76 outpatients with DSM-III dysthymic disorder entered into a trial at two centers. Subjects were preponderantly female, had insidious onset at an early age, and had depressions of moderate severity; 96% also met the DSM-III criteria for major depressive disorder at the time of presentation. Sixty percent had a history of persistent depressive symptoms sufficient to meet criteria for major depression for longer than two years. Markedly favorable responses occurred in 45% of imipramine-treated (n = 29) and 12% of placebo-treated (n = 25) patients and, respectively, 59% and 13% of those who completed the study. Imipramine produced significant advantage in measures of depressive symptoms, global severity of illness, and self-rated social and vocational function. Recovered patients experienced remission from both long-standing symptoms and deficits as well as more recently exacerbated aspects of their syndrome. Patients with pure dysthymic disorder of a mild, subsyndromal type were uncommon in these clinical settings. However, anti-depressant medication was effective for many moderately severe chronic depressions, which had previously been untreated or undertreated, presumably related to misdiagnosis.

Preliminary data are presented from the NIMH Collaborative Study on the psychobiology of depression, biological studies, dealing with relationships between the pre-treatment levels of the neurotransmitter metabolites 3-methoxy-4-hydrophenethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and the subsequent therapeutic response of depressed patients to imipramine or amitriptyline. Eighty-seven depressed patients were studied during pre-treatment and treatment periods. It has been found that (1) both low pre-treatment urinary MHPG and low CSF 5-HIAA values are associated with a response to imipramine; these relationships were not artefacts due to sex or age; (2) there were no significant relationships between pre-treatment urinary MHPG, CSF MHPG, 5-HIAA, or HVA values and the subsequent response, or failure of response, to amitriptyline; (3) there was not a bimodal distribution for CSF 5-HIAA. For both males and females, there were positive and statistically significant correlations between CSF MHPG and urinary MHPG; for the females, there were positive and significant correlations between both urinary and CSF MHPG and CSF 5-HIAA. The theoretical and practical implications of these findings are discussed.

It has been suggested that there are altered levels of norepinephrine or other neurotransmitters at functionally important receptors in patients with depressive disorders. This hypothesis is difficult to study in the human central nervous system. However, noradrenergic function can be assessed indirectly with peripheral-blood lymphocytes used as a model of the beta-adrenergic receptor complex. We found that drug-free inpatients with endogenous depression had lower isoproterenol-stimulated cyclic AMP levels in intact lymphocytes than did healthy control subjects (3.9 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01). The density and affinity of beta-adrenergic receptors were similar in controls and depressed subjects (beta-receptor number, 5.4 +/- 0.7 and 5.3 +/- 0.8 fmol per 10(6) cells; binding affinity, 106 +/- 7.6 vs. 99.2 +/- 11.4 pM, respectively). When the depressed patients were subdivided by psychomotor manifestations, binding characteristics were indistinguishable among the subgroups. However, a significant reduction in beta-adrenergic responsiveness was observed in patients with psychomotor agitation, as compared with controls (2.6 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01), but not in patients with psychomotor retardation (5.8 +/- 1.1 pmol per 10(6) cells, P less than 0.05). Thus, the desensitization of beta-adrenergic receptors was correlated more closely with the severity of psychomotor agitation than with the overall severity of depression.

Monoamine oxidase (MAO) inhibitors are effective antidepressants whose use is limited because of unwanted side effects and the possibility of a tyramine-induced hypertensive crisis (cheese reaction). (-)-Deprenyl (the official nonproprietary name for this substance is selegiline), a selective MAO type B inhibitor, may be safer and have fewer side effects, but its antidepressant efficacy is uncertain. A double-blind placebo-controlled study was carried out in depressed outpatients who were treated with (-)-deprenyl in an MAO type B selective dose range and at a higher nonselective dose range. (-)-Deprenyl did not have a statistically significant antidepressant effect after three weeks of treatment at doses of 10 mg/d. However, after six weeks and at higher doses (averaging about 30 mg/d for the second three weeks), (-)-deprenyl was superior to placebo in antidepressant effect with a positive response rate of 50% vs 13.6% and with a 41% reduction in the Hamilton Depression Rating Scale mean score vs 10% in the placebo-treated group. No hypertensive crises were seen. The rate of occurrence of side effects with (-)-deprenyl was no greater than with placebo. It was concluded that (-)-deprenyl is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of nonselective MAO inhibitors.

We had previously reported that imipramine was superior to placebo for the treatment of chronic depression. As a part of that study, we subsequently investigated clinical and demographic variables which might be associated with favorable or poor outcome for treatment with imipramine or placebo. Results are reported herein. Eight-six patients were entered and 53 completed an 8-week protocol. Outcome was assessed based on a 6-week, double-blind treatment phase, which followed a 2-week, single-blind placebo phase. Outcome was not found to significantly relate to demographic variables, severity or course of depression, diagnostic subtype, symptom profile, or DST results. Some modest associations were found between 'neurotic' personality traits and poor outcome. Results are discussed and compared with prior studies of prediction of tricyclic antidepressant response in both acute and chronic depressions.

The authors review the history of the concept of dysthymia and the literature on the epidemiology, course, and treatment of chronic depression. They present a critical discussion of DSM-III and DSM-III-R criteria for dysthymic disorder. On the basis of this review, they suggest that future revisions of the nomenclature include further subcategorization of chronic depressive disorders and that the term "dysthymic disorder" be reserved for chronic depressive disorders with an insidious onset at an early age. The relationships between dysthymic disorders and personality disorders and the response of subcategories of chronic depression to different treatment modalities need to be researched.

This retrospective study compared the treatment responses of 34 primary, unipolar depressives without psychotic features and 30 with psychotic features. Patients were diagnosed by Research Diagnostic Criteria and received trials of tricyclic antidepressants, antipsychotics, the combination of the two, electroconvulsive therapy, or placebo and psychotherapy. Only three of 18 psychotic patients vs. 17 of 23 nonpsychotic patients responded to antidepressants alone. Electroconvulsive therapy and the combination of antipsychotic and antidepressant medication gave better responses. These data suggest that major depressive disorder with psychotic features is best considered as a distinct subtype rather than a severe variant of major depression.

Plasma drug concentrations and clinical response were measured in two groups of hospitalised depressed patients, who received amitriptyline or imipramine double-blind, in a dosage of 250 mg for four weeks. Virtually no significant linear or curvilinear relationships were found between any plasma measure and any measure of clinical response. Modest but significant direct relationships were found between age and concentration of parent drugs but not demethylated metabolites. Blood drug level measurement therefore appears to be of little value in monitoring drug treatment of depressed in-patients.

The authors compared the effects of 6 weeks of imipramine treatment with 6 weeks of placebo treatment on social and vocational impairment in chronic depression. Imipramine was associated with significantly greater pre- to posttreatment improvement of social-vocational impairments in chronic depression, suggesting that these impairments may have represented affective symptoms rather than characterologic deficits.

This study examined relationships between depressive subtypes, clinical-behavioral characteristics, and hypothalamic-pituitary-adrenocortical (HPA) function in 132 hospitalized depressed patients. There were significant positive correlations between several pre- and postdexamethasone plasma cortisol measures and anxiety, psychomotor disturbance, distressed expression, and sleep disturbance. Few significant relationships were seen between illness severity and HPA function. Virtually no endocrine differences were seen between endogenous and nonendogenous subtypes or between psychotic and nonpsychotic subtypes. These results and the previous literature suggest a profile of depressed patients with HPA overactivation; they are likely to be anxious, to have sleep and psychomotor disturbances, to have lost weight in the current episode, and to be older.

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.

The authors reviewed the charts of 61 manic-depressive outpatients maintained on lithium for 6--75 months for relationships between clinical outcome and various demographic, clinical, and pharmacological variables. Good outcome (50% reduction in episode frequency) did not correlate with any demographic or most natural history variables. A history of frequent episodes was correlated with decreased episode frequency but not with a lower percentage of prophylaxis failure during follow-up. A nonsignificant trend toward decreasing episode occurrence with increasing duration of lithium maintenance was present. Depression occurred considerably more frequently than manic episodes at adequate maintenance plasma lithium levels. More medication noncompliance was found among patients who experienced both manic and depressive relapses.

Overnight 1 mg dexamethasone suppression tests were performed on 37 hospitalized patients with unipolar major depression and 13 psychiatric controls: 62% of the depressives and 38% of controls failed to suppress below 6 micrograms/dl of plasma cortisol at least once on the day after dexamethasone. Specificity for depressive diagnosis was only 62% but rose to 100% when a plasma cortisol value of 10 micrograms/dl was used as the criterion for normal suppression. Depressed patients were significantly more likely to show normal suppression if they were under age 65 (56% vs. 24% in the geriatric sample). Other demographic and clinical variables examined in the depressed sample did not assort by suppressor status.

To determine the clinical significance of thyroid function abnormalities in patients maintained on lithium, the authors evaluated the relationships of thyroid function tests to clinical response to lithium and side effects from lithium in 20 outpatients meeting DSM-III criteria for major affective disorder. No significant relationships were found between baseline thyroid function tests and clinical response. Thyroxine (T4) and triiodothyronine uptake ratio (T3UR) within the normal range were found to be associated with complaints of lethargy and cognitive impairment. Thirteen subjects were followed prospectively for 6 months with monthly evaluations of affective state, side effects, and occurrence of relapse. Thyroid function tests were repeated at the final visit. Final and mean T3 levels within the normal range were found to be significantly lower in patients who relapsed, and mean T3 level was inversely correlated with affective state as measured by mean scores on the Hamilton Rating Scale for Depression and the Young Mania Rating Scale.