Biomedical subjects
Publications and source records attributed to J C Nelson.
Two patients had grand mal seizures following abrupt discontinuation of short-term treatment with alprazolam. Alprazolam's pharmacokinetic and clinical properties are discussed in relation to withdrawal reactions.
Results of liver function tests in 46 depressed patients changed little during treatment with desipramine and were uncorrelated with drug plasma levels. The findings suggest that tricyclic-associated hepatitis, rather than being dose dependent, is an uncommon, idiosyncratic phenomenon.
Studies of desipramine in depressed inpatients are reviewed and indications for the use of the drug in clinical practice, as well as selection of patients for research, are discussed. The relationship between plasma desipramine concentrations and response is examined in melancholic and elderly patients, and in those with delusional depression. Major adverse reactions and subjective complaints during studies of desipramine treatment are reviewed. Few side effects were associated with elevated plasma desipramine levels. The clinical significance of 2-OH-desipramine levels was studied, but measurement of this metabolite did not enhance understanding of the drug's effects. A new technique for rapid dose adjustment is presented, for which desipramine appears to be particularly well suited.
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The clinical utility of 2-hydroxydesipramine (2-OH-DMI) measurements was evaluated by examining the relationship of 2-OH-DMI concentrations in plasma to clinical outcome and side effects in depressed inpatients treated with desipramine (DMI). Studies were performed in responders and nonresponders to treatment and in patients experiencing subjective side effects or major adverse reactions necessitating interruption of treatment. Unlike DMI concentrations, 2-OH-DMI concentrations did not correlate with response. Summing the concentrations of parent drug and metabolite (DMI + 2-OH-DMI) did not improve the correlation over that achieved with DMI alone. Neither DMI, 2-OH-DMI, nor their sum correlated with subjective side effect totals or major adverse reactions. While our data do not permit any conclusions regarding the clinical activity of 2-OH-DMI, they suggest that its routine measurement in plasma is not likely to be useful in the management of depression.
Steady-state plasma concentrations of desipramine (DMI), unconjugated 2-OH DMI, and total 2-OH DMI were measured in 82 depressed inpatients, 35 of whom were concurrently receiving a phenothiazine or butyrophenone antipsychotic drug. In the patients not on an antipsychotic, the ratio of unconjugated metabolite to parent varied from 0.01 to 1.5, with a median of 0.48, and was inversely related to the parent drug level. Antipsychotic drug was associated with higher DMI levels and a lower proportion of OH-metabolite (median, 0.23). In both groups the unconjugated form accounted for only about 10% of the total metabolite. No relationship of age, sex, drinking history, or smoking to DMI or 2-OH DMI levels was found.
Recent clinical studies have reported rapid improvement following administration of lithium to depressed patients who are unresponsive to tricyclic antidepressants. The clinical value of lithium augmentation would be greatest in subtypes of depression refractory to tricyclic treatment, such as delusional depression. The authors describe the results of a preliminary study of lithium augmentation in six patients with delusional depression who were unresponsive to combined neuroleptic-tricyclic treatment. Of the six, three had a dramatic response, two had a more gradual response, and one was unresponsive. The authors discuss alternative mechanisms of lithium action in these patients.
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Major adverse reactions interrupting drug therapy during treatment of 84 patients with desipramine hydrochloride were studied to determine their relationship to desipramine plasma concentrations and other clinical variables. The frequency of adverse reactions was higher in patients over 60 years old (39%), and in patients also receiving antipsychotic medications (32%), but low in patients under 60 years old (7%). Desipramine plasma concentrations in patients having side effects did not differ significantly from those in patients without side effects. Steady state desipramine plasma concentrations did not increase with age. Symptomatic orthostatic hypotension, the most common side effect encountered, occurred early in treatment at low desipramine plasma concentrations. Other side effects, usually described as anticholinergic, occurred exclusively in the 34 patients receiving both desipramine and antipsychotic drugs. The concentration of 2-hydroxy-desipramine, the total concentration of 2-hydroxy-desipramine and desipramine, and the ratio of 2-hydroxy-desipramine to desipramine were not higher in 11 patients having side effects than in a comparison group without side effects.
The relationship of desipramine hydrochloride plasma concentration and antidepressant response was determined in 30 depressed inpatients treated for three weeks with desipramine. All patients had a nondelusional unipolar depression, met DSM-III criteria for major depressive episode with melancholia, and had a Hamilton score of 18 or greater after one week of hospitalization without medication. Eighty-nine percent of the patients with plasma concentrations above 115 ng/mL responded, in contrast to 14% of those with concentrations below this level, a significant difference (Fisher's exact test, P less than .001). Ten initial nonresponders were converted to responders when dosage increase raised desipramine plasma concentration to 125 ng/mL or above. In clinical practice a plasma concentration of 125 ng/mL would be a useful guideline as a threshold above which desipramine is likely to be effective.
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Eleven randomly hydrated patients with metastatic malignancies received iv bolus chemotherapy. Serial observations of plasma antidiuretic hormone (ADH), serum osmolality, blood pressure, and presence of nausea or emesis were made over the next 3-4 hours. Group 1 (four patients) had no nausea or emesis and no change in ADH, osmolality, or mean blood pressure. Group 2 (seven patients) had nausea and emesis following chemotherapy, with an increase in mean ADH from a baseline level of 5.53 pg/ml to a peak after emesis of 33.83 pg/ml. Group 2 had no significant increase in osmolality or decrease in mean blood pressure before emesis. ADH levels increased 0-40 minutes before emesis and peaked 28-115 minutes (mean, 66) after emesis. Emesis caused by chemotherapy agents is associated with rapid, significant increases in plasma ADH levels, independent of changes in osmolality or blood pressure.
A case of probable exacerbation of an undiagnosed diabetic uropathy by a tricyclic antidepressant in a 67-year-old man with hypothyroidism, diabetes mellitus, and recurrent major depressive disorder is reported. The presumed mode of interaction is discussed and pertinent literature reviewed. It is emphasized that the clinician must be alert to the possibility of psychotropic drugs producing physiologic changes that can interact with or aggravate preexisting disorders.
The hepatic porphyrias are inborn errors of porphyrin and haem biosynthesis characterized biochemically by excessive excretion of delta-aminolaevulinate (ALA), porphobilinogen and other intermediates in haem synthesis. Clinical evidence has implicated iron in the pathogenesis of several types of genetically transmitted diseases. We investigated the role of iron in haem metabolism as well as its relationship to drug-mediated induction of ALA synthase and haem oxygenase in acute and chronic iron overload. Acute iron overload in rats resulted in a marked increase in hepatic haem oxygenase that was associated with a decrease in cytochrome P-450 and an increase in ALA synthase activity. Aminopyrine N-demethylase and aniline hydroxylase activities, which are dependent on the concentration of cytochrome P-450, were also decreased. In contrast, in chronic-iron-overloaded rats, there was an adaptive increase in haem oxygenase activity and an increase in ALA synthase that was associated with normal concentrations of microsomal haem and cytochrome P-450. The induction of ALA synthase in chronic iron overload was enhanced by phenobarbital and allylisopropylacetamide, in spite of the fact that these agents did not increase haem oxygenase activity. Small doses of Co2+ were potent inducers of the haem oxygenase in chronic-iron-overloaded, but not in control, animals. We conclude that increased hepatic cellular iron may predispose certain enzymes of haem synthesis to induction by exogenous agents and thereby affect drug-metabolizing enzyme activities.
The DSM-III criteria for melancholia are intended to define an endogenomorphic subcategory of major depressive episode for which somatic treatment is usually required. One hundred twenty-three inpatients having a major depressive episode were examined retrospectively to determine the ability of the melancholia criteria to identify patients observed to have an autonomous syndrome during the first week of hospitalization and to distinguish them from patients observed to be responsive to psychosocial intervention without drug treatment. The melancholia criteria correctly classified 77% of the sample. In comparison with the primary affective disorder criteria, the melancholia criteria appeared to be selective; fewer responsive patients were falsely identified. The predictive values of individual symptom criteria were examined. Of the current symptom criteria, two observed signs, lack of reactivity and psychomotor change, were most useful for making the autonomous-responsive distinction.