Abstract. Abrupt cessation of clonidine treatment in hypertensive patients may precipitate a withdrawal syn- drome. Since this drug is likely to be more widely.
Psychopharmacology
Psychopharmacology (1984) 84: 58 - 63
9 Springer-Verlag 1984
Catecholamine metabolism during clonidine withdrawal Peter R. Martin 1'2, Michael H. Ebert 2, Edna K. Gordon 2, Herbert Weingartner 3, and Irwin J. Kopin 2 1 Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20205, USA 2 Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20205, USA 3 Laboratory of Psychology and Psychopathology, National Institute of Mental Health, Bethesda, MD 20205, USA
Abstract. Abrupt cessation of clonidine treatment in hypertensive patients may precipitate a withdrawal syndrome. Since this drug is likely to be more widely prescribed to normotensive patients with neuropsychiatric diseases, we studied neurochemical, cardiovascular, and behavioral changes upon placebo substitution in seven patients receiving clonidine (6 ~g/kg/day for 3 weeks) for treatment of alcohol amnestic disorder. Urinary excretion of all major catecholamine metabolites returned to pretreatment levels 3 - 5 days after discontinuing clonidine, without significant overshoot. The percentage increase during clonidine withdrawal of the norepinephrine metabolite normetanephrine was greater than were those of vanillylmandelic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the epinephrine metabolite metanephrine. Excretion of the dopamine metabolites homovanillic acid and 3-methoxytyramine did not change. Total plasma MHPG, heart rate, and mean arterial pressure were significantly elevated above pretreatment values 72 h after the last dose of clonidine. There was an enhancement of episodic memory compared to predrug values but no other behavioral changes were noted during clonidine withdrawal. These findings are consistent with augmented catecholamine release and central noradrenergic activation which may produce psychopathology in some psychiatric patients during clonidine withdrawal. Key words: Clonidine - Withdrawal - Normetanephrine - Metanephrine - Vanillylmandelic acid - 3-Methoxy-4-hydroxyphenylglycol
Selective depression of central noradrenergic activity by the a2-adrenergic agonist clonidine hydrochloride (Houston 1981) provides the rationale for using this agent to treat patients with several neuropsychiatric disorders. Clonidine attenuates opiate (Gold et al. 1978) and alcohol (Walinder et al. 1981) withdrawal syndromes. Clonidine may be useful in the management of bipolar (Jouvent et al. 1980) and unipolar (Jimerson et al. 1980) affective disorder, in psychotic illnesses (Freedman et al. 1980; Jimerson et al. 1980), and in generalized anxiety, including agoraphobia (Hoehn-Saric et al. 1981). Patients with narcolepsy (Putkonen and Bergstrom 1981), Tourette's syndrome (Cohen Offprint requests to: P. R. Martin, National Institute of Health, Building 10 Room 3B-19, 9000 Rockville Pike, Bethesda, MD 20205, USA
et al. 1979), tardive dyskinesia (Freedman et al. 1980), and Korsakoff's psychosis (McEntee and Mair 1980) may also benefit from clonidine treatment. In the future, therefore, clonidine or similar drugs may be clinically indicated for the treatment of other disorders than hypertension. Recent self-administration studies in the rhesus monkey suggest the possibility of clonidine abuse and dependence in humans and the need to better understand behavioral aspects of the clonidine abstinence syndrome (Woolverton et al. 1982). Cardiovascular function during the clonidine withdrawal syndrome has been actively studied in patients with all grades of hypertension (Houston 1981) and in several animal models (Thoolen et al. 1981), but not in normotensive subjects. Therefore, we investigated neurochemical, behavioral, and cardiovascular changes upon abrupt discontinuation of clonidine in normotensive patients who were receiving this drug for treatment of alcohol amnestic disorder (AAD) (McEntee and Mair 1980). Materials and methods Seven men (53-67 years of age), who were long-term patients at the United States Soldiers' and Airmen's Home, Washington, D.C., and met DSM III diagnostic criteria for AAD (American Psychiatric Association 1980), consented to participate in an approved trial of clonidine hydrochloride in the treatment of memory impairment (Martin et al. 1983). Only one patient had consumed alcohol within 6 months prior to hospital admission and all patients were abstinent during the period of hospitalization. None of the patients had significant cardiovascular, renal, endocrine, or hepatic disease at the time of study, nor psychiatric illnesses other than a history of alcohol dependence. Supine blood pressures prior to clonidine treatment were below 140/85 mm Hg in all patients. All patients were drug-free for at least 3 weeks prior to the study and received a low-monoamine diet during this period. Patients received clonidine in three divided doses (7 AM, 3 PM, 11 PM) during weeks 2 - 4 and placebo during weeks 1 and 5 of the 5-week study. During weeks 2 and 4, patients received 6 ~tg/kg/day clonidine and, during week 3, four of seven patients tolerated a daily dose of 12~tg/kg/day clonidine whereas the remaining three patients continued to receive the lower dose. The patients and all staff, except P. R. Martin, were unaware of whether placebo or active medication was being administered. Supine blood pressure (BP) and heart rate (HR) were measured five times daily (just before and 2 h after drug or
59 placebo administration) after the patient had been recumbent for 5 min. Mean arterial pressure (MAP) was calculated as diastolic BP + (systolic BP - diastolic BP)/3. During days 3 - 5 of each week of the study, patients were evaluated on two occasions using the modified Brief Psychiatric Rating Scale (BPRS) and the Hamilton Psychiatric Rating Scale for Depression (HPRSD) (Guy 1976). A battery of research tests developed to evaluate learning and memory of recently acquired information (episodic memory) and access and use of information in knowledge (semantic) memory (Weingartner et al. 1981) were administered before the study and during placebo administration, clonidine treatment, and clonidine withdrawal. Complete daily urine collections were obtained for analyses of catecholamine metabolites, starting on day 4 of each of the first 4 weeks and for the first 6 days after withdrawal. Only those urine specimens containing more than 1 g creatinine and greater than 900 ml were considered as complete 24-h collections. For every patient, individual urinary metabolite excretion rates for each phase of the study were taken as the average of three complete 24-h collections. Blood samples were obtained at 9 AM on day 3 of each week of the study with subjects remaining supine for 30 min after insertion of a forearm IV catheter. The last sample was obtained 72 h after the last dose of clonidine. Free 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured after plasma extraction, whereas total MHPG (free plus conjugated fractions) was determined after hydrolysis of extracted plasma samples with a glucuronidase-arylsulfatase preparation (Glusulase, Endo, Garden City, NY). The urinary catecholamine metabolites vanillylmandelic acid (VMA), MHPG, normetanephrine (NM), metanephrine (M), homovanillic acid (HVA), 3-methoxytyramine (MT) as well as plasma M H P G levels were all determined by gas chromatography-mass spectrometry using deuterated internal standards (Gordon et al. 1974). Each patient's physiologic measures, psychological test scores, and metabolite data were averaged for each of the three phases of the study. This was considered valid because the measured parameters did not change significantly between weeks 1 and 3 of clonidine treatment. Values during each phase of the study were evaluated using one-way analyses of variance (ANOVA) for repeated measures or nonparametric statistical tests when requirements for ANOVA were not satisfied (Komogorov-Smirnov test, Siegel 1956). Results are means _+ SEM unless otherwise stated. Results
After discontinuation of clonidine, urinary NE metabolite excretion rose and reached a peak during days 3 - 5 (Fig. 1). During days 3, 4, and 5 of the drug withdrawal period, total NE metabolites were double those found during clonidine treatment (P < 0.005). NM, VMA, and MHPG increased in each patient, i.e., the mean values increased by 210% + 39.0% (P < 0.002), 104% + 15.6% (P < 0.001), and 105% + 33.2% (P < 0.02), respectively, compared to the clonidine treatment period (Fig. 2). The increase in M excretion (26.0% + 8.4%; P < 0.03) during clonidine withdrawal compared to treatment values was less than those observed for NE metabolites. During withdrawal, none of the urinary NE or epinephrine (E) metabolites was significantly elevated above the predrug placebo level (Fig.
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