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A model of therapeutic lag
Affective :Lnd Related Disorders
BIOL PSYCHIATRY 1990;27:41A- 179A
157A
261 A MODEL OF THERAPEUTIC LAG
R.J. Katz, Ph.D. Pharmaceuticals Division, CiBA-GEiGY Corporation, Summit, NJ 07901. Virtually all antidepressant, antiobsessional, and neuroleptic drugs when given orally, are characterized by a prolonged (2-S week) latency to onset of clinically significant effects. A variety of chronic monoamine (alpha2- and het.a-adrenergic serotonergic 5-HT2)-receptor and post-translational adaptations have been proposed to explain therapeutic lag. Because many of the reference compounds are lipoph,.'lic, we examined this physiochemical property as a potential contributor to lag. We propose a model of lag based upon a single saturable pool of body fat, with effect, onset dependent, in part based on previous attainment of equilibrium in fatty tissues. To test this model, we examined the effects of the antidepressanVantiobsessional drug clomipramine hydrochloride in a recently completed trial in obsessive compulsive disorder. Obesity, defined by physical examination and Metropolitan height/weight tables served as an independent variable, and onset of therapeutic efficacy was examined as a function of increased body fat. Consistent with the model, obesity further retarded the initial (1-3 week) clinical effects of clomipramine in OCD. Although these findings do not suggest that receptor adaptations necessarily are inconsequential, they do suggest that physiochemical properties such as lipophilicity ~,ay significantly contribute to some of the variance associated with lag effects i.a..
262 POSTURAL CHANGES IN HEART RATE DURING
IMIPRAMINE TREATMENT V.K. Yeragani, M.D., R. Pohl, M.D., R. Balon, M.D., C. Ramesh (by invitation), D. Glitz, M.D. (by invitation) Lafayette Clinic, Detroit, Michigan 48207. Postural changes in heart rate and blood pressure were studied during a postural test in panic disorder (n = 6) and depressed (n = 14) patients before and l week and 3 weeks after treatment with the tricyclic antidepressant drug imipramine. There were 6 males ami 14 females, and the mean age was 35. 1 "4- 6.6 years. All patients were on the same dose of imipramine (mean 69 mg) at week I and week 3. In both groups of patients, compared with the pretreatment cc ndition, imipramine treatment significantly enhanced the tachycardia upon standing (17.1 -.+ 8.3 versus ~3.5 - 13.2; t = 86; df = 16; p < 0.02) and also significantly exaggerated bradycardia during the change from standing to supine posture (17.9 ± 10.2 versus 30.6 - 16.3; t = 3.34; df = 14; p < 0.005) at week 1. There was no significant change in resting heart rate from week I to week 3 of imipramine treatment (82.3 ± 14.6 versus 83.8 ± 16.7; t = 0.64; df - 15). There was a significant decrease of the tachycardic response to standing from supine posture from week I to week 3 of imipramine treatment (23.1 ± 13.5 versus 17.7 .4- 89.9; t = 2.85; df = 15; p < 0.02). Thh finding may suggest a decrease in betaradrenergic response to imipramine treatment at week 3 compared to week I.
263 CHANGES IN URINARY TYRAMINE SULFATE EXCRETION
PREDICT TREATMENT RESPONSE IN DEPRESSION Joel L. Steinberg, M.D., Mark H. Zielinski, M.D., Paul Orsulak, Ph.D., Lisa B. Cates, B.S., Joachim D. Raese, M.D. Schizophrenia Research Center, Veterans Affairs Medical Center, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75216. Urinary tyramine sulfate (TY-SO4)after an oral TY loading dose was measured in normal controls and major depressives who met RDC criteria for endogenous, nonendogenous, and probable endogenous subtypes of depression. Endogenous depressives had significantly lower mean TY-SO4 excretion values than the other groups combined. There was no correlation of TY-SO4 excretion and Hamilton-D (HAM-D) scores after 1
BIOL PSYCHIATRY 1990;27:41A- 179A
157A
261 A MODEL OF THERAPEUTIC LAG
R.J. Katz, Ph.D. Pharmaceuticals Division, CiBA-GEiGY Corporation, Summit, NJ 07901. Virtually all antidepressant, antiobsessional, and neuroleptic drugs when given orally, are characterized by a prolonged (2-S week) latency to onset of clinically significant effects. A variety of chronic monoamine (alpha2- and het.a-adrenergic serotonergic 5-HT2)-receptor and post-translational adaptations have been proposed to explain therapeutic lag. Because many of the reference compounds are lipoph,.'lic, we examined this physiochemical property as a potential contributor to lag. We propose a model of lag based upon a single saturable pool of body fat, with effect, onset dependent, in part based on previous attainment of equilibrium in fatty tissues. To test this model, we examined the effects of the antidepressanVantiobsessional drug clomipramine hydrochloride in a recently completed trial in obsessive compulsive disorder. Obesity, defined by physical examination and Metropolitan height/weight tables served as an independent variable, and onset of therapeutic efficacy was examined as a function of increased body fat. Consistent with the model, obesity further retarded the initial (1-3 week) clinical effects of clomipramine in OCD. Although these findings do not suggest that receptor adaptations necessarily are inconsequential, they do suggest that physiochemical properties such as lipophilicity ~,ay significantly contribute to some of the variance associated with lag effects i.a..
262 POSTURAL CHANGES IN HEART RATE DURING
IMIPRAMINE TREATMENT V.K. Yeragani, M.D., R. Pohl, M.D., R. Balon, M.D., C. Ramesh (by invitation), D. Glitz, M.D. (by invitation) Lafayette Clinic, Detroit, Michigan 48207. Postural changes in heart rate and blood pressure were studied during a postural test in panic disorder (n = 6) and depressed (n = 14) patients before and l week and 3 weeks after treatment with the tricyclic antidepressant drug imipramine. There were 6 males ami 14 females, and the mean age was 35. 1 "4- 6.6 years. All patients were on the same dose of imipramine (mean 69 mg) at week I and week 3. In both groups of patients, compared with the pretreatment cc ndition, imipramine treatment significantly enhanced the tachycardia upon standing (17.1 -.+ 8.3 versus ~3.5 - 13.2; t = 86; df = 16; p < 0.02) and also significantly exaggerated bradycardia during the change from standing to supine posture (17.9 ± 10.2 versus 30.6 - 16.3; t = 3.34; df = 14; p < 0.005) at week 1. There was no significant change in resting heart rate from week I to week 3 of imipramine treatment (82.3 ± 14.6 versus 83.8 ± 16.7; t = 0.64; df - 15). There was a significant decrease of the tachycardic response to standing from supine posture from week I to week 3 of imipramine treatment (23.1 ± 13.5 versus 17.7 .4- 89.9; t = 2.85; df = 15; p < 0.02). Thh finding may suggest a decrease in betaradrenergic response to imipramine treatment at week 3 compared to week I.
263 CHANGES IN URINARY TYRAMINE SULFATE EXCRETION
PREDICT TREATMENT RESPONSE IN DEPRESSION Joel L. Steinberg, M.D., Mark H. Zielinski, M.D., Paul Orsulak, Ph.D., Lisa B. Cates, B.S., Joachim D. Raese, M.D. Schizophrenia Research Center, Veterans Affairs Medical Center, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75216. Urinary tyramine sulfate (TY-SO4)after an oral TY loading dose was measured in normal controls and major depressives who met RDC criteria for endogenous, nonendogenous, and probable endogenous subtypes of depression. Endogenous depressives had significantly lower mean TY-SO4 excretion values than the other groups combined. There was no correlation of TY-SO4 excretion and Hamilton-D (HAM-D) scores after 1